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

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

Cardiac long noncoding RNA

Transdifferentiated cardiomyocytes Fibroblasts  cardiomyocytes

Solving genetics for undiagnosed diseases @Genetics, KKH / NUH Rare disease genomics 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

October 2000

N.A.S.S.H.

Normo-aldosterone Spironolactone-sensitive Hypertension

Grand Staff Round University of Cambridge School of Medicine

70 90 110 130 150 170 190

180/105 176/100 144/80

Atenolol Lisinopril Doxazosin Bisoprolol Irbesartan Doxazosin Spironolactone

80 120 160 200 240

230/110 192/91 165/93 126/88

Atenolol Enalapril BFZ Indoramin Lacidipine Clonidine Hydralazine Atenolol Co-amilozide Spironolactone

70 100 130 160 190 220

200/100 208/116 128/80 144/90

Losartan Bisoprolol Losartan Bisoprolol Spironolactone Spironolactone Atenolol Enalapril BFZ Indoramin Amlodipine Hydralazine

A c B

Clinical Vignettes

aldo renin N aldo renin *Ratio  Ratio  adenoma

Spi piro ronolacton

• lactone-sens

sensitive tive hype pertens rtension ion

*ratio=aldo/renin

Conn’s

adenoma  K+ nor K+ N aldo renin Ratio Normal normal scan

N. N.A.S.S.H S.S.H.

normal scan

age Pre-BP aldo renin AR ratio CT/ MRI Present Meds Present BP KB 55  186/92 210 0.5 420 normal Spironolactone 25bd Doxazosin 8bd Irbesartan 300od 146/80 SW 48  164/96 170 0.7 243 normal Spironolactone 25bd Irbesartan 300od 128/88 JG 63  180/104 160 0.6 266 pending Spironolactone 50bd 164/78 IZ 58  210/104 260 0.6 433 pending Spironolactone 25bd Irbesartan 300od 180/84 AS 64  150/95 230 0.3 767 normal Spironolactone 25bd 124/80 CA 62  200/100 220 0.2 1100 pending Spironolactone 75od Enalapril 10od 144/80 GK 54  205/90 240 0.2 1200 pending Spironolactone 25bd Doxazosin 2od 130/80 MB 66  180/102 280 0.2 1400 normal Spironolactone 25bd Amlodipine 10od 148/98 JG 53  198/120 360 0.2 1800 pending Spironolactone 25bd 147/90

No Normo mo-aldo aldosteron sterone e Spirono ironolac lactone tone-sens sensitive tive hypertension pertension [N.A.S.S A.S.S.H.] .H.]

Low

• w-re

renin in hype pertens rtension ion

Spiro ronola nolactone ctone responsive ponsive Thiazide zide responsive ponsive

Conn’s N.A.S.S.H S.S.H. Low

• w re

renin HTN HTN

The Red House Surgery, Cambridge

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 Atenolol 100mg od, Lisinopril 20mg bd 170/100 mmHg Heart/lungs clear fundi normal urine dipstix normal

Rx Rx O/E O/E

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) AR ratio 4250 50   (<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

420 / 279 348 / 310 >330 300 0 / >1480 480

Ad Adre renal venous us samp mpli ling

aldosterone / cortisol (280-650 nmol/l)

• Normalised ratio

unilat: 3x contralat contralat: suppressed (suprarenal IVC)

• Confirm catheter position

cortisol: 2x suprarenal IVC right hepatic tributaries 481 / 1455

Mr r WI

70 90 110 130 150 170 190

180/105 176/100 144/80

mmHg

Atenolol Lisinopril Bisoprolol Irbesartan Amlodipine Spironolactone

Mr r WI

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 Atenolol 100mg, Enalapril 20mg, bendrofluazide 2.5mg, indoramin 12.5mg, lacidipine 60mg, hydralazine 50mg bd, clonidine 75ug bd 230/110 mmHg Heart/lungs clear fundi normal urine dipstix trace protein

Rx Rx O/E O/E

Mrs rs DB DB

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

Mrs rs DB DB

80 120 160 200 240

230/110 192/91 165/93 126/88

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

Mrs rs DB DB

mmHg

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 Bisoprolol 5mg, Losartan 100mg 220/116 mmHg Heart/lungs clear fundi normal urine dipstix normal

Rx Rx O/E O/E

Mr r PR

Electrolytes normal Aldosterone190 N (100-450 pmol/l) renin (PRA) 0.4

↓

(0.5-3.1 pmol/ml/hour) AR ratio 475 475 N (<750 units)

Mr r PR

70 100 130 160 190 220

200/100 208/116 128/80 144/90

Losartan Bisoprolol Losartan Bisoprolol Spironolactone Spironolactone

Mr r PR

mmHg

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.

St Study dy Plan

Trial of Spironolactone 50 mg/day CT of adrenals Diagnosis nosis of PHA 400 800 sBP > 20 mmHg 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

Clin Med, 2005

A l d

• s

t e r

• n

e / R e n i n R a t i

• N
• f o

b s e rv a tio n s

2 8 5 6 8 4 1 1 2 1 4 1 6 8 1 9 6 2 2 4 2 5 2 2 8 3 8 2 4 6 8 1 1 2 1 4 1 6 1 8 2 2 2 2 4 2 6 2 8 3 3 2

72.7 17.2

Prevalence of ratio: (<400) (400-800) (>800)

12.3

Di Distribution tribution of

• f al

aldos

• ste

terone/r rone/reni enin n ra rati tio

Be Beta-bl blocke

• ckers

rs but t not other her Rx affect ct aldo/re

• /renin

in ra ratio

Sc Scattergr tergram am of aldost ster eron

• ne

e and re renin levels ls

Plasma ma re renin pre redicts icts re respon ponse se to spiron ronola

• lactone

ctone (e (excludin uding g patien ients ts on BB BB)

Conclusion usions Low-ren renin HTN N !!!

Renin and hypertension

Spironolactone responsive Thiazide/ CCB Betablocker/ ACEI or ARB < 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 Prima mary ry causes ses

Cambridge UK: AB/CD rule

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

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

Cambridge ABCD rule

A C B D < 50 yrs > 50 yrs

Cambridge ABCD rule

A C B D < 50 yrs > 50 yrs

1- blockers

• Doxazosin

Centrally acting

• Moxonidine

Potent vasodilators

• Minoxidil

Lisinopril Candesartan Bisoprolol Amlodipine Nifedipine LA Co-amilozide Bendrofluazide

Cambridge Hypertension Clinic Protocol

Routine investigations

• U+E+Cr
• cholesterol
• random glucose
• ECG
• 24h ur VMA
• renin (aldosterone)
• echocardiogram

Clinical examination

• primary causes: RAS, Cushing’s, renal disease
• target organ damage: fundoscopy, urinstix

Primary causes: suspect in young HT primary hyperaldosteronism and others

Cambridge Hypertension Clinic Protocol

Routine investigations

• U+E+Cr
• cholesterol
• random glucose
• ECG
• 24h ur VMA
• renin (aldosterone)
• echocardiogram

Clinical examination

• primary causes: RAS, Cushing’s, renal disease
• target organ damage: fundoscopy, urinstix

Primary causes: suspect in young HT primary hyperaldosteronism and others Captopril Mag3 Plasma catecholamines Renal angiography

Renin based proforma for treating resistant hypertension

ACEi 

Sartan &  blocker

Add CCB or Thiazide Measure Renin Sartan & βblocker Normal/High + ACEi Low Thiazide 

Spironolactone Spironolactone + Sartan

Add

long-acting  -blocker

ACEi + {Thiazide or CCB}

Incorporated into the BHS IV guidelines (2004)

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 Obvious left adrenal adenoma on CT, but AVS technically unsuccessful Small is beautiful: sub-cm APA caused BP 240/140 mmHg despite 5 drugs Aldo-Producing Adenomas

Conn’s

• riginal

tumour >4cm ~2cm APA Sub-cm micro APA

Clin Endocrin 2015

PA-CURE Study

Troy Puar, Consultant Endocrinologist, CGH

• 1. The use of 11C-metomidate

PET-CT in Sg

• 2. Prevalence of low renin HTN

Audrey Wong, Consultant Physician, NUH

Am J Hypertens 2014

• 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 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

Spironolactone responsive Thiazide/ CCB Betablocker/ ACEI or ARB < 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 Prima mary ry causes ses

Cambridge UK: AB/CD rule

Hypertension, 2009

AB/CD rule

2004 2004

AB/CD rule and improvement in UK BP control

Thank you