Blood Pressure Variability: The Good And The Bad

Sola Aoun Bahous

LAU Medical Center – Rizk Hospital

Master Course in HypertensionMarch 2015

Blood Pressure Variability: Mechanisms and Clinical Relevance

1. BPV: a physiological characteristic of the cardiovascular system

2. Assessment of BPV

3. Prognostic importance of BPV

4. BPV reduction: CV risk lowering independent of BP reduction?

Blood Pressure Variability: Mechanisms and Clinical Relevance

1. BPV is a physiological characteristic of the cardiovascular system

2. Assessment of BPV

3. Prognostic importance of BPV

4. BPV reduction: CV risk lowering independent of BP reduction?

Blood Pressure Variability: Mechanisms and Clinical Relevance

Weber M, J Hypertens 2006

A. Zanchetti, Residual Risk in Treated Hypertension In Special Issues in Hypertension, 2012, A. Berbari and G. Mancia

A. Zanchetti, Residual Risk in Treated Hypertension In Special Issues in Hypertension, 2012, A. Berbari and G. Mancia

A. Zanchetti, Residual Risk in Treated Hypertension In Special Issues in Hypertension, 2012, A. Berbari and G. Mancia

Blood Pressure Parameters

• What BP parameter to use?

• What anatomical site?

• What time to consider?

BP Variability

• Site variability

• Time variability

BP is a highly variable parameter

Intra-arterial BP recording in a subject lying supine, at rest

Time Variability of Arterial BP

19 22 1 4 7 10 13 16 19

0

100

200mm Hg

Mancia G, Parati G, J Hypertens 1990;8(suppl. 7):S1-S13

Within-individual BPV over time varies from one patient to another

Rothwell PM. Lancet. 2010;375:938-948.

Patient 1 with lower BPV Patient 2 with higher BPV

Weeks

40

60

80

100

120

140

160

180

200

220

Bloo

d pr

essu

re

(mm

Hg)

1 2 3

SBP

DBP

40

60

80

100

120

140

160

180

200

220

Bloo

d pr

essu

re

(mm

Hg)

1 2 3Weeks

BP Variability

• “Rather than representing a “background noise” or a phenomenon occurring at random, these variations are known to be the result of complex interactions between extrinsic environmental and behavioral factors and intrinsic cardiovascular regulatory mechanisms (neural central, neural reflex, and humoral influences) that are not yet completely understood”. (Parati G. et al, Nat. Rev. Cardiol. 2013; 10:143)

BP Variability Subtypes

• Short-term BPV (within 24hrs):– Very short: beat-to-beat– Short: within a 24-h period (minute-to-minute,

hour-to-hour, and day-to-night)

• Long-term BPV:– Day-to-day– Visit-to-visit– Seasonal

BP Variability: Mechanism

Short-time Variability:• Beat-to-beat• Baroreceptors• Respiration• Sleep• Chemoreceptors

Mechanisms: central and reflex autonomic modulation, reduced arterial compliance, humoral effects, rheological factors, emotional factors, behavioral influences/physical activity, sleep, postural changes.

BP Contour

BP Variability: MechanismLong-time Variability:• Day-to-day (behavioral changes)

• Visit-to-visit• Seasonal: SBP and DBP have been reported to

be lower during summer and higher during winter. Inappropriate down dosing of drugs leads to increase in night-time BP with hot weather reported in some studies.

Mechanisms: less well studied. Behavioral factors, increased arterial stiffness, poor BP control, or inconsistent office readings.

Blood Pressure Variability

• BPV is a known and natural characteristic of blood pressure

• BPV is secondary to mechanisms of varied nature

• Divided into short-term and long-term

24h Intra-Arterial BP

19 22 1 4 7 10 13 19

Hours

0

100

200

mmHg

Protective Damaging

Different Prognostic Impact of Nocturnal BP Fall and Short Term BPV

Mancia G, Parati G 1983

Blood Pressure Variability: Mechanisms and Clinical Relevance

1. BPV is a physiological characteristic of the cardiovascular system

2. Assessment of BPV3. Prognostic importance of BPV4. BPV reduction: CV risk lowering

independent of BP reduction?

Assessment of BPV

• Indices: SD, CV, day-to-night BP changes, ARV, residual BPV, trough-to-peak, night-to-day

• Setting: – Continuous beat-to-beat BP recordings: SD– Repeated OBPM: SD, CV, ARV– 24h ABPM: SD, CV, residual BPV, ARV, day-to-night, trough-to-

peak, night-to-day– HBPM: SD and CV– Visit-to-visit: SD and CV

• Smoothness Index: used to assess the amplitude and distribution over time of BP reduction by treatment. 24-hourly BP changes/SD

Assessment of BPV

• CV: (SD/BP)100• Residual BPV: fast fluctuations that remain

after exclusion of the slower components of the 24h profile through spectral analysis

• ARV: (BP2-BP1) + (BP3-BP2) + (BP4-BP3) + etc. /N

• Day-to-night: Dipping status• Night-to-day: Morning surge

Circadian Variability of BP

• Beat-to-beat variability

• Day-to-night variability– Dippers– Non-dippers– Reverse dippers/risers– Excessive dippers

• Night-to-day variability: morning surge

Nocturnal Dipping Status

1. The correct time period of sleep and awakening should be considered

2. Poor reproducibility of the classification of hypertensives into dippers and nondippers based on 1 ABPM

Nocturnal Dipping Status

Mechanisms underlying nondipping status:• Persistence of sympathetic drive at night• Reduced sensibility of baroreceptors at night• Volume overload in specific conditions• Autonomic dysfunction

Nocturnal Dipping Status

• Nondipping status is associated with CV risk

• Nocturnal BP independently predicts outcome

• Extreme dipping is associated with higher risk for cerebral and retinal ischemia

• Chronotherapy?

Morning Surge• No consensus on the definition and threshold value of

pathological MBPS

• Usually assessed using the ABPM

• Exaggerated surge is associated with TOD and leads to increased risk of CV events or death

• Weekly and seasonal variations in MBPS: augmented on Mondays and in winter

• MBPS increases with age, HTN, glucose intolerance, inflammation, alcohol, smoking , stress, etc…

Kazuomi Kario, In Special Issues in Hypertension, 2012, A. Berbari and G. Mancia

Blood Pressure Variability: Mechanisms and Clinical Relevance

1. BPV is a physiological characteristic of the cardiovascular system

2. Assessment of BPV

3. Prognostic importance of BPV

4. Reduction of BPV on top of BP reduction may represent a new target for treatment to further reduce cardiovascular risk (?)

Prognostic Importance of BPV

Clinical Relevance of Short-Term BPV

Study

Parati, 1987Palatini, 1992Mancia, Parati, 2001Liu, 2003Frattola, Parati, 1993Sander, 2000Dawson, 2000Kikuya, 2000Pringle, Parati, 2003Mena, 2005Mancia, 2007 Tatasciore, Parati, 2007Parati, 2009Hansen, 2010

Design

Cross-sectionalCross-sectionalCross-sectionalLongitudinal (rats)LongitudinalLongitudinalLongitudinalLongitudinalLongitudinalLongitudinalLongitudinalCross-sectionalLongitudinalLongitudinal

Endpoint

TOD scoreTOD scoreCarotid IMTCardiac /renal damageLV mass (echo)Carotid IMT / CV eventsDead / dependency (after acute stroke)CV mortalityStrokeCV eventsCV mortalityCarotid IMT, LVMICV eventsOnly DBP for CV events / stroke

Clinical Relevance of 24h BP Variability

Mancia G, Short-Term and Long-Term Blood Pressure Variability, In Special Issues in Hypertension, 2012, A. Berbari and G. Mancia

Relation Between Risk of Stroke and Morning BP Surge In The Ohasama Study

Metoki et al. Hypertension.2006

Stroke total Ischaemic Haemorrhagic0

1

2

3

4

5

I I

I

II II IIIII

III

III

IVIV

IV

V

V

V

Quintiles of morning BP surge

RR

p = 0.12 p = 0.94 p = 0.03

N = 1430

Incidence of CV events, 24 h BP and Night/day SBP ratio in Syst Eur study

Staessen JA, Parati G et al. for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

JAMA 1999; 282: 539-546

Nocturnal BP Dipping

CV Fatal Events in Relation with DBP Variability

Mancia G, Short-Terma and Long-Term Blood Pressure Variability, In Special Issues in Hypertension, 2012, A. Berbari and G. Mancia

CV Events CV Events

10

9

8

7

6

5

4

3

2

10

9

8

7

6

5

4

3

2

7 9 11 13 15 17 5 7 9 11 13

150

133

123

114

105

np=8938 ne=1049

Parv=0.03 Pbp<0.001

89

79

73

67

60

np=8938 ne=1049

Parv=0.04 Pbp<0.001

10-year risk of combined

CV events, %

Average real variability (mmHg)

10-year risk associated with ARV24 at different levels of 24-h BP

10-year risk associated with ARV24 at different levels of 24-h BP

Systolic BP Diastolic BP

Hansen TW et al, Hypertension 2010; 55: 1049-57

Prognostic Importance of BPV

Clinical Relevance of Long Term BPV

17164 M

SD of SBPSD of SBP SD of DBPSD of DBP

CV

mor

tali

ty (

%)

Follow-up (years)

15

10

5

0

0 3 6 9 12 0 3 6 9 12

Q4

Q3

Q2Q1

Q4

Q3

Q2Q1

Home measurements once a day for 4 weeks

Follow-up (years)

CV

mor

tali

ty (

%)

15

10

5

0

Max

Min

Max

Min

Kikuya et al. Hypertension. 2008

OHASAMA STUDY - Kaplan-Meier Survival Estimates for CV Mortality across Quartiles of Day-by-Day BP Variability (HBPM)

(n= 2455)

Visit-to-visit Variability and Risk of Stroke and Coronary Events in UK-TIA and ASCOT-BPLA

Rothwell PM et al., Lancet 2010; 375: 895-905

BPV: Types and Prognostic Significance

Parati G et al. Nature Reviews Cardiology. 2013.10:143-155

Blood Pressure Variability: Mechanisms and Clinical Relevance

1. BPV: a physiological characteristic of the cardiovascular system

2. Assessment of BPV

3. Prognostic importance of BPV

4. BPV reduction: CV risk lowering independent of BP reduction?

DRUG A

DRUG B

BP

(m

m H

g)

DrugAdministration

Peak Trough

Peak Trough

24 h SD of BP

BP

(m

m H

g)

Target for Research

WHICH ANTIHYPERTENSIVE DRUG DO REDUCE BP VARIABILITY BEST?

PM Rothwell et al., www.thelancet.com/neurology Published online March 12, 20106083 P

Within-visit variability of systolic blood pressure in ASCOT-BPLA

Placebo L50 R10 V80 V160 T40 T80 A50.0

0.2

0.4

0.6

0.8

1.0

1.2SBP

DBP

Sm

ooth

ness

inde

x

§ §

††

§

§

†

‡

*

*

L50, losartan 50 mg; R10, ramipril 10 mg; V80–160, valsartan 80–160 mg; T40–80, telmisartan 40–80 mg; A5, amlodipine 5 mg

*p < 0.05; †p < 0.01; ‡p < 0.001; §p < 0.0001 vs telmisartan 80 mg

(n = 160) (n = 50) (n = 712) (n = 197) (n = 430) (n = 140) (n = 2033) (n = 206)

Parati G et al J.Hypertens 2010; 28: 2177-2183

Comparison of Monotherapies

P=0.04

P=0.01P=0.03

P=0.08

*

*

*

*

SB

P v

aria

bilit

y (m

mH

g)

**

Amlodipine significantly reduces short-term BPV

Yi Zhang, et al. Hypertension. 2011;58:155-160.

Placebo

Candesartan

Indapamide

Amlodipine

Does Treatment-Induced Reduction in BPV Improve Outcome? Target for Research

• Studies in rats showed improvement outcome related to TOD

• Conclusive clinical studies are pending

BPV – Need of additional studies

• Average BP levels and/or BPV?

• Short or Long Term BPV?

• Which measure of BPV to choose?

• Relationships with physiological variables

(e.g. endothelial function, SpO2, arterial

stiffness)?

• BPV in Risk Stratification?

BPV – Need of additional studies

• Is a drug-induced reduction in BPV accompanied by a reduction in event rate?

• Do different drug classes have a different effect on BPV and on outcome?

• Is there enough evidence to consider BPV as a new target for treatment?

Conclusions

• Average BP levels and/or BPV?

• Short or Long Term BPV?

• Which measure of BPV to choose?

• Relationships with physiological variables

(e.g. endothelial function, SpO2, arterial

stiffness)?

• BPV in Risk Stratification?

BothMainly short

SD

Some correlations exist?

Conclusions

• Is a drug-induced reduction in BPV accompanied by a reduction in event rate?

• Do different drug classes have a different effect on BPV and on outcome?

• Is there enough evidence to consider BPV as a new target for treatment?

?

Probably CCBs and long-acting ARBs?

?

Conclusions

• 24 h BP values more closely related to TOD and future events than office readings

• Higher 24 h BP Variability = Higher CV risk

• Long lasting CCBs seem to score best in reducing short term and long term BPV

• Prospective outcome studies needed to confirm that treatment-induced reduction in BPV improves outcome

Lebanese Variability

Thank You