Dr Patrick Gladding - GP CME North/Sun_Plenary_0815_Gladding_GPCM… · Dr Patrick Gladding ... •USS –right renal hydronephrosis •ACEi - ?nephrectomy 56. ... •Advanced lipids

Dr Patrick GladdingCardiologist and Internal Medicine

North Shore Hospital

Auckland

8:15 - 8:40 Personalised Hypertension Management and Genomics

Personalised Hypertension

Managemement and Genomics

Dr. Patrick Gladding, MBChB, FRACP, PhD

Ascot Cardiology

Hypertension update

• New Guidelines

• Definitions and treatment thresholds

• Global risk, investigations (Pulse wave velocity) and monitoring (mHealth)

• Targets – SPRINT trial

• Lifestyle interventions (Functional Foods)

• Genomics and Personalised Care

Outline

Secondary causes of Hypertension

Cushings syndrome

Aortic coarctation

• Office BP• White coat hypertension

• Ambulatory 24-hr BP (ABPM)• Masked hypertension

• Home blood pressure monitoring• Increased granularity

• White coat hypertension

• Feedback

• Dietary/Lifestyle and drug n=1 trials

• Adherence

• Personal control

JAMA. 2014;312(8):799-808

• 552 patients• 9mmHg SBP reduction with self-Mx

• 2 emerging techniques in echo to improve detection of end-organ damage:

1) LV strain; Deformation of the LV vs EF

2) LV mass

• 76 yr old man –Supine HTN orthostatic hypotension (~50mmHg)

• Arterial stiffness indicates lower central BP

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Hypertension update

Guidelines – take with a grain of salt

• Increased risk of CV events with very low salt intake

• Guidelines based on averaging population

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N Engl J Med 2014

• JNC 8• Goal for people > 60 yrs should be a SBP < 150, DBP < 90

• For fit elderly patients, a high DBP (>90 mm Hg) was associated with a 50% increase in mortality

• By contrast, for frail elderly patients, a low DBP was associated with a 50% increased risk of dying during 15 year follow-up period

1466 older men and women

“The ultimate goal is personalized treatment so that we can avoid overtreatment of the frail, and undertreatment of the fit.”

• 9361 patients (age, ≥50) with SBP of 130 to 180 mm Hg and high cardiovascular (CV) risk

• One or more: CV disease, CKD EGFR 20–59 mL/minute/1.73 m2, 10-year Framingham CV risk ≥15%, or age ≥75

• Patients with diabetes and stroke were excluded. • Patients were randomized to either intensive or standard treatment (systolic

BP targets, 120 or 140 mm Hg, respectively)• The trial was terminated early after median follow-up of 3.3 years• The primary composite outcome (MACE) occurred in 5.2% of intensive-

treatment patients and 6.8% of standard-treatment patients (P<0.001)

• “First, the results should not be considered a mandate for people to run out and get treated so their blood pressures are below 120.

• Second, the potential benefits of lowering blood pressure must be weighed against harms.

• Third, we need more information about the balance of risks and benefits for each person so that the choice can be personalized.”

Gladding et al. Personalized Medicine Journal. June 2015 ,Vol. 12, No. 3, Pages 297-311

Renal denervation therapy

• SYMPLICITY-3:• Renal denervation therapy

doesn’t work, for unselected patients with HTN

• Renal artery stenosis

Age directed vs Renin directed Rx

Individualise Rx based on other comorbidities

Spironolactone for Resistant HTN

http://80.36.73.149/almacen/medicina/oftalmologia/enciclopedias/duane/pages/v3/ch013/005f.html


J Clin Pharmacol 1994;34:1173-1176

Personalised Medicine in practice

Wireless telemedicineGenomics

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Era of Mobile Health

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Advanced ECG

• WiFi based ECG

• Ultraportable, $3,500

• Deconvolutes ECG components

• Advanced pattern recognition, artificial intelligence

• ECG biological age

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https://upload.wikimedia.org/wikipedia/commons/e/e5/NASA_logo.svg

https://upload.wikimedia.org/wikipedia/commons/e/e5/NASA_logo.svg

Advanced ECG for general practice

• Sensitive, high sampling frequency, accurate.

Case

• 43 year old man with dyspnoea, BP 220/140

Case

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British Journal of General Practice 2007; 57: 191–195

BMJ 1996;312:222

• A-ECG LVSD Sensitivity 93-95%, Specificity 95%

• Southern X reimbursed

• 70 year old male with minor exertional angina symptoms

• Some exertional component

• PHx: CABG 1997, HTN, dyslipidaemia, home stress, OSA (unable to tolerate CPAP), BPH

• Previously trialed on:• Lisinopril, Perindopril, Celiprolol, Metoprolol,

• Bendrofluazide, Frusemide, Hydrochlorothiazide, Amiloride, Spironolactone, Isradipine, Nifedipine,

• Diltiazem, Doxazosin, Clonidine patches, Losartan and Candesartan

Case: 70 year old man with HTN


Disease and Gene networks


• Angiotensin Type I gene, which carries an odds ratio of 7.3 for developing hypertension• RAAS drugs

• Poorly functional drug metabolism genes (CYP3A5)

• Homozygous for the MTHFR C677T mutation• 15% of the population unable to metabolise folate and B12

• increased risk for gastrointestinal cancer, hypertension, coronary artery disease

• Riboflavin reduces BP in RCT

• Heterozygote for HFE (H63D), haemochromatosis he has increased oxidative stress which will impact on BP and CAD risk

• ADH1B*1 variant indicating a targeted benefit to drinking red wine to improve glucose homeostasis

• ECG pattern demonstrating presence of coronary artery disease

• 1st ECG show proximity to early LVSD

• 2nd ECG shows trend away from LVSD towards health

• Managed with self-directed BP Rx, over 9 months

• Candesartan 4mg bd

• Riboflavin

• WiFi BP monitor

• Office BP 184/90 to BP 148/80


Conclusion

• Hypertension is common, often called the “Silent Killer”

• Requires personalised Care taking into account • Global risk• Age and comordities• Guidelines not always applicable to the individual patient

• Emerging technologies for investigation of end-organ disease

• Lifestyle, diet, prevention paramount• Functional foods• Feedback, mHealth, Internet of Things (IoT)

• Limited new drug treatments, or procedures though these will be targeted

• Emerging role of genomics (not yet fully advocated)

Interactive Session: Hypertension and Personalised Care

Dr. Patrick Gladding, MBChB, FRACP, PhD

• 53 year old man with atypical chest discomfort

• Nonsmoker, Unknown FHx

• Dyslipidaemia• TC 7.1• HDL 1.5• LDL 4.4• Trigs 4.8

• Exercises, moderate build

• Normal ECG

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Case: 53 year old man

What test would you request?

•Advanced lipids Lp(a)•CIMT•CAC•ETT•CTCA

45


What test would you request?

•Advanced lipids Lp(a)•CIMT•CAC•ETT•CTCA

46


52 year old GP

• 53 year old man with atypical chest discomfort

• Unknown FHx

• Dyslipidaemia• TC 7.1

• HDL 1.5

• LDL 4.4

• Trigs 4.8

• Exercises, moderate build

• CT coronary angiogram

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LAD LCx

CV Risk overestimated by calcs

48Ridker P, Cook N. Ann Intern Med. 2015;162(4):313-314

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Primary prevention trials; NNT 10 years was 66 with low genetic risk, 42 in intermediate genetic risk, and 25 in high genetic risk in JUPITER/ASCOT

THREE-FOLD DECREASE IN NNT WITH GENETIC RISK SCORE

Genetic risk score

Labounty TM, Gomez MJ, Achenbach S, et al. Body mass index and the prevalence, severity, and risk of coronary artery disease: an international multicentre study of 13 874 patients. European Heart Journal Cardiovascular Imaging. 2013;14(5):456-463. doi:10.1093/ehjci/jes179.

• Genetic risk score 1.3 (intermediate)

• NNT 42 to prevent 1 event over 10 years

• Visualisation of genetic risk

• Personalised statin Rx• Rosuvastatin 20mg achieved LDL 2.2

• + Paleo diet achieved LDL 1.1

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Case: Value of genomic risk assessment

Case: 26 year old with HTN on home BP monitor

• Checked BP on friend’s mother’s home BP machine

• Measurement “high”

• ABPM 169/101

• No other PMHx

• Maternal Grandparents had HTN, Gfather had ESRF and HD

• Normal diet, no illicit drugs

• Mother did not have pre-eclampsia

• Normal FBC, Cr, TSH.

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Ubiquitous home BP monitoring


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What investigations would you order?

1. Urinalysis – sediment, microalbumin/Cr ratio2. Renin/Aldosterone levels3. Echocardiogram4. Renal artery USS5. All of the above


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What investigations would you order?

1. Urinalysis – sediment, microalbumin/Cr ratio2. Renin/Aldosterone levels3. Echocardiogram4. Renal artery USS5. All of the above


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Differential diagnosis for his age

•Secondary hypertension much more likely from structural reasons e.g. coarctation, PCKD, but acute renal injury, nephritis but also endocrine (hyperaldosteronism)•FHx – PCKD? Hereditary HTN

Case: Value of ubiquitous home BP monitoring

• Checked BP on friend’s mother’s home BP machine

• Measurement “high”

• ABPM 169/101

• USS – right renal hydronephrosis

• ACEi - ?nephrectomy

56

Case: 56 year old man with longstanding hypertension

• 56 year old man with longstanding hypertension

• GORD, dyslipidaemia, TIA 2014?, abnormal LFTs - 3-4L beer/day

• Palmar desquamation reaction to indapamide

• ABPM average BP 145/87, whilst on Candesartan 16mg od

• Renal USS – no renal artery stenosis, post void residual 80mls

• Echocardiogram: Mild basal septal hypertrophy

• Renin 744 (4 – 46), Aldosterone 134 (60 – 1,000) on ARB



59

How would you manage him?

1. Renin directed Rx - Bb2. Add bendrofluazide3. Add amlodipine4. Counsel regarding EtOH5. 1 or 3, and 4

Spironolactone for Resistant HTN




60Spironolactone for Resistant HTN

How would you manage him?

1. Renin directed Rx - Bb2. Add bendrofluazide3. Add amlodipine4. Counsel regarding EtOH5. 1 or 3, and 4



• Renin is a red herring, cannot be relied upon whilst taking antiHTN meds, especially RAAS blockers• Renin is also elevated in chronic EtOH

• Indapamide is a “thiazide-like diuretic”, as it bendrofluazide ?Class effect with desquamation

• Age on the cusp of the NICE guidelines so could get ACEi (<55yrs) or CCHB (>55yrs) however the big problem is in the ABPM


Case: Value of 24hr ABPM and diurnal measures

Focus on alcohol

Worrying diastolic nadir 40mmHg

Case: 56 year old man abstaining from alcohol

Case: 61 year old GP

• 61 year old GP, Hx of HTN on Rx

• 12L ECG “normal” AECG abnormal/CAD and biological age

• Coronary angiogram mild-moderate CAD64

Journal of Hypertension 2014, 32:1229–1236

What are the red arrows pointing to?

1.Acute coffee intake2.Conn syndrome3.Work stress4.Normal diurnal variation5.Phaeochromocytoma

Case – 61 year old GP

What are the red arrows pointing to?

1.Acute coffee intake2.Conn syndrome3.Work stress4.Normal diurnal variation5.Phaeochromocytoma

Case: 61 year old GP

Case – 61 year old GP

• Work stress is associated with HTN

• Concurrent CAD Rx to lower target?

• Manage causes of stress, mindfulness67


Case: 56 year old wife of GP

• ABPM BP 166/97

(Grade II HTN)

• Was on Amlodipine 5mg

• Drug withheld 2 weeks:• Renin 22, Aldo N

• Green mussel extract, celery extract

Emotional stress

Journal of Hypertension 2014, 32:1222–1228J Clin Hypertens (Greenwich). 2014 Jan; 16(1): 54–62.

What is the next course of action?

1.Increase dose of CCHB2.Bb3.ACEi or ARB4.Diuretic5.Spirinolactone





What is the next course of action?

1.Increase dose of CCHB2.Bb3.ACEi or ARB4.Diuretic5.Spirinolactone





Case – 56 year old wife of GP

• Was on Amlodipine 5mg

• ABPM BP 166/97

• Renin 22, Aldo N

• Green mussel extract, celery extract

• Px Chlorthalidone12.5mg od

• Pranayama

Emotional stress


Pranayama

J Clin Hypertens (Greenwich). 2014 Jan; 16(1): 54–62.

Case: 48 year old woman

• 48 year old woman with depression on Venlafaxine 225mg

• Mild dyslipidaemia

• Prior Hx of right sided breast cancer, partial mastectomy

• FHx of premature stroke

• Office BP 145/99

• Normal Cr, ECG, renin/aldosterone ratio

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How would you better define risk in view of BP?

•Advanced lipids Lp(a)

•CIMT

•CAC

•ETT

•CTCA74


How would you better define risk in view of BP?

•Advanced lipids Lp(a)

•CIMT

•CAC

•ETT

•CTCA75


What is the cause of her mild hypertension?

76


Case: Drug induced HTN

• 48 year old woman with depression started Venlafaxine, BP 145/99

• Genomics indicated ADE

• WiFi BP max 133/95

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Case:29 year old woman

•29 year old woman, otherwise well, father adopted

•Normal weight, no EtOH

•No added salt, good sleep quality

•Office BP 140/90 on OCP78


What would you do next?

1. Stop the OCP, alternative Rx and retest her BP

2. 24-hr ABPM

3. Renin/Aldosterone

4. Renal USS

5. Renal denervation therapy

What would you do next?

1. Stop the OCP, alternative Rx and retest her BP

2. 24-hr ABPM

3. Renin/Aldosterone

4. Renal USS

5. Renal denervation therapy

Case: Incidental genomics

• 29 year old woman, otherwise well, father adopted

• Office BP 140/90 on OCP

• ABPM 132/85

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• 3-4 cups of coffee per day associated with increased risk of MI and HTN in poor metabolisers


deltaF508 carrier

Genetic counselling

Prenatal screening

Case 54 year old man

• 54 year old man presents with MI

• HTN with known hypertensive retinopathy, mild-mod LVH on Echo• BP 217/119 in 2014, started on Felodipine 10mg od

• Smoker

• Occasional methaphetamine user

• BP 170/90 on chlorthalidone 12.5mg od

• Moderate CAD on coronary angiography

• ASA/Ticagrelor/Statin/Bb/Chlorthalidone

Case 54 year old man - Potassium

Losartan + Thiazide

MI

Atypical CP, dyspnoeaAdmitted to hospital

TnI <15

Felodipine 10mg odAtypical CP, dyspnoeaAdmitted to hospital

Dx GORD

Took P went to ED

F/up clinicChlorthalidone

stopped

3.5

3.42.9

Renin <2 (4 – 46), Aldosterone 600 (60 – 1,000)

K supp

Spironolactone

What is the diagnosis?

1.Acute coffee intake2.Surreptitious thiazide use3.Conn syndrome4.Methaphetamine related hypokalaemia5.Phaeochromocytoma


What is the diagnosis?

1.Acute coffee intake2.Surreptitious thiazide use3.Conn syndrome4.Methaphetamine related hypokalaemia5.Phaeochromocytoma

Case: Conn Syndrome

Saline suppression testRenal vein sampling

Personalised Medicine in practice

Wireless telemedicineGenomics

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Case: 76 yr old man – Supine HTN orthostatic hypotension (~50mmHg)

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• 76 year old man with PHx CVA, Oesophageal Ca, Ivor Lewis

• Syncope on CCHB, Bb, ACEi, Terazosin (Tamsulosin)

• Abnormal 12L high fidelity ECG

• 3D A-ECG near purple sphere (LVH) and early LVESD, confirmed on echocardiography and MRI (EF 51%)

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• Atrial bradyarrhythmia and autonomic dysfunction

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Heart Rate VariabilityPoincaré Plot

Normal example

Multiple complex signals Abnormal spectrum


90

• Daytime and Nocturnal HTN, no dipping

• High cardiovascular risk


Arterial stiffness indicates lower central BP

91

• Upgraded to WiFi enabled home BP monitoring & email guidance (n=1 trial and chronotherapy)

• Clonidine patch + nocturnal clonidine 25ug, ACEi

• Internet monitoring shared with your GP practice92


Internet of Things (IoT)

• Synchronised handwriting and audio recording, with playback

• WiFi and Cloud enabled; Evernote, Google Drive, Dropbox

• Patient notes and handwriting

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Click

https://www.evernote.com/shard/s170/sh/c883f400-ab24-4a04-af9f-dd656713c09d/6172520ad8d53d547bb88417acbb708a

Case: GI cancer and HTN

• He was homozygous for rs13129697 (SLC2A9) and heterozygous for rs7917983 (TCF7L2) indicating a higher risk of gout and diabetes with thiazides

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Hypertension. 2013;61:1302-1308.

Thank you

Palpitations

• 62 year old female palpitations

• PHx EtOH 30u/wk, dyslipidaemia (TC 7.6)

• Ix• 12L ECG

• Mg, K, TSH

• Holter

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• Holter report and diary

• LOW YIELD

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Era of Mobile Health

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Anticoagulation

• Warfarin

• Dabigatran

• Apixiban

102

Atrial Fibrillation Genomics

• AF risk prediction

• Efficacy of DC cardioversion

• Anti-arrhythmic drugs

• Warfarin and dabigatran

• AF ablation

103

Thank you

Documents

Dr Patrick Gladding - GP CME North/Sun_Plenary_0815_Gladding_GPCM… · Dr Patrick Gladding ... •USS –right renal hydronephrosis •ACEi - ?nephrectomy 56. ... •Advanced lipids