SCN, suprachiasmatic nuclueus ATVB 2007;27:1694

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1 Clinical Aspect of Morning Blood Pressure Surge Eung Ju Kim Korea University Guro Hospital Cardiovascular Center Seoul, Korea

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3 Circadian Rhythm Daily behavior cycles that of are physiology driven by and an endogenous oscillator with a period of approximately (dies or diem). (circa-) one day

4 = SCN, suprachiasmatic nuclueus ATVB 2007;27:1694

5 CV or hemodynamic parameters such as HR, BP, endothelial function, and fibrinolytic activity exhibit variations consistent with circadian rhythm.

6 Diurnal Variation of BP g) Blo ood pre essure (mm H Lancet 1978;1(8068): Circ Res 1983;53: Sleep Time of awakening 80 18:00 22:00 02:00 06:00 10:00 14:00 18:00 Time of day

7 Early Morning BP Surge 200 Untreated hypertensives Morning Normotensives Morning ssure (mm mhg) Blood pre Systolic (mean+s.e.) 50 Diastolic (mean+s.e.) Time of day (hours) Time of day (hours) Lancet 1978;1:

8 Various Types of BP Daytime BP? Dipping Pattern? Nighttime BP? Morning Surge? Clinic BP? 24 Hr Average BP? Home BP? Variability of BP?

9 Definition There is no universally recognized definition of the morning surge Kario et al. Circulation 2003;107:1401 Leary et al. JHTN 2002;20:865 4Hr 4Hr

10 Morning BP Surge & Subclinical Organ Damage

11 MBPS Causes TOD MBPS hemodynamic stress TOD High MBPS more likely to have LVH BP in the morning is a better predictor than office BP of: the decline in GFR albuminuria in patients with type 1 diabetes albuminuria in patients with type 2 diabetes J Hypertens 2004;22: Clin Exp Hypertens 2002;24: Diabetes Care 2002;25: Diabetes Care 2003;26:

12 Early Morning Attenuation of Endothelial Function in Healthy Humans Circulation 2004;109:

13 Morning BP Surge or Reactivity and LVH MBPR = MBPS / (sum of 2-h activity after arising) 0.5 Am J Hypertens 2005;18:

14 Morning BP Hyper-Reactivity and LVH Am J Hypertens 2005;18: Morning BP Reactivity it was independently associated with cardiac hypertrophy

15 Morning BP is a Better Predictor than Clinic i BP of Albuminuria i in Type 2 DM Sens 100% Specificity 68% Sens 49% Specificity 75% Sens 18% Specificity 85% Threshold 135mmHg Sens 43% Specificity 73% Threshold 85mmHg Diabetes Care 2002;25:

16 CV Events Occur More Frequently In the Morning!

17 The Early Morning BP Surge Coincides with peak time of cardiovascular complications Sudden death Acute myocardial infarction Typical angina pectoris Silent ischemia Total tlischemic i burden Ischemic stroke Variant angina pectoris (02:00-04:00) Platelet aggregability 06:00-12:00 Lancet. 1988;2: ; Am Heart J. 1989;118: ; Stroke. 1989;20: ; Circulation. 1989;80: ; Ter Arkh 2000;72:

18 Circadian Variation of Acute CVD M I Thrombotic Stroke SCD T I A Circulation Apr;79(4):

19 Circadian Patterns of Onset of Symptoms of Stroke A: all B: Ischemic C: Hemorrhagic D: TIA Stroke May;29(5):992-6

20 Morning Excess of AMI and Sudden Cardiac Death Am J Cardiol Jun 1;79(11):1512-6

21 Morning Peak of VT Detected by ICD Episodes of VT Circulation 1995;92: 1203

22 Morning BP Surge is Independently Associated With

23 MBPS is Independently Associated With CV Complications Baseline : Untreated 507 HTN Then treated Multivariate i t analysis Mean 7yr f/u SBP change on rising CV Cx: MI, Angina, CVA, SCD, CRF, HF, PAD, AAA, Carotid stenosis Journal of Hypertension 2004, 22:

24 MBPS is Independently Associated With Stroke 519 older HTN Mean 41mo f/u Circulation. 2003;107: % / 10mmHg After controlling for age, sex, BMI, 24h SBP

25 Why Morning Surge?

26 Vascular MBPS CV Events ; Mechanism Remodeling Steep BP surge Cardiac Remodeling oscillatory shear stress in vessel wall Other CV arterial stiffness Risk Factors IMT + α CV in LVH Morning Events!

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28 MBPS Oxidative Stress HTN N= 31 RO OS From PMN From MNC Hypertens Res 2005;28:

29 in Carotid Plaque of MBPS Hypertension 2007;49: Hypertensives

30 UP in Carotid Plaque of MBPS Hypertension 2007;49: Hypertensives

31 Circadian Variation of PAI-1 and tpa Activities J Am Coll Cardiol, 1998; 32:

32 Therapeutic Strategies to Control MBPS

33 Hypertension Awareness, Treatment and Control iduals (% ) Indivi 80 USA Canada 70 Ita ly Sweden 60 Poor rates of control* in western countries Spain England 50 Germany Aware Treated Controlled Aware Treated Controlled * Threshold of SBP/DBP 140/90 mm Hg Wolf-Maier et al. Hypertension 2004;43:10 17

34 In Pts with Controlled Office BP; Also During Morning Hours? 70 Controlled (morning < 135/85mmHg) Not controlled 60 Pati ients (%) ACAMPA study J-MORE Redón et al. Blood Press Monit 2002;7: Kario et al. Circulation 2003;108:72e 73e 34

35 Early Morning BP Surge as a Target for Therapy Consider Pharmacokinetic profile with morning dosing Underlying mechanisms for MBPS

36 A Therapeutic Blind Spot With Current Therapy in the Morning One of the suggested reasons for morning hypertension in treated subjects. Insufficient duration of action (short T1/2) of antihyertensive vulnerable. drugs, leaving patients

37 Chronotherapeutic ti Tx Strategies t Choose drug with long trough-to-peak ratios, during the morning surge Extended-release, dosing Twice daily doses Coupled with a diuretic half-life life ensuring delayed-onset, with high coverage bedtime

38 Half-lives lives of Various Blood Pressure Medications Hours Amlo Telmi Lisino Cande Valsar Verapa Losar 2 J Clin Hypertens 2008;10:

39 Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour BP Missed Dose Mancia et al AJC 1999: 84; 28S

40 Duration of Action by Trough:Peak Ratio 6 Blood Pressure Change mmhg Peak Placebo Drug Trough Hours after dosing 24

41 Effects of Time of Administration on Diurnal Changes of BP 0-1 Change -2 of SBP, mmhg - 3 Day Nig ht 24 hour m g bid - 5 1m g qd Poirier J Clin Pharm 1993: 33:832 Trandolapril

42 Adherence to Treatment Greater with Once-daily Dosing * *** erence (% %) Adh erence (% %) Adh O n ce-d aily T w ice-d aily O n ce-d aily M u le d aily OD BID OD Multiple doses * P<0.05 vs twice-daily dosing *** P<0.001 vs multiple daily doses Clin Ther 2002;24:

43 Targeting Mechanisms Responsible for MBPS Sympathetic Nervous System Morning BP surge Platelet hyperactivation Endothelial cell dysfunction Blood viscosity it Renin-Angiotensin-AldosteroneAldosterone System Morning BP surge

44 SNS RAAS

45 Effects of α-blockade on the Morning Surge of BP No Rx Doxazosin Dosing Kario, Pickering, et al Am J Hypertens 2004;17; 668

46 Effects of Bedtime Dosing of Centrally Acting α2-agonists 2 i t on Morning HTN morning Guanabenz evening Clonidine Usefulness of sympathoinhibitory hibit action, &/or of night-time dosing in controlling Morning HTN J HTN 2003;21:

47 Regression of Carotid Atherosclerosis by Controlling Morning BP by α1/ß Antagonist SBP -5 mmhg -10 Clinic i Day Night Morning Carotid IMT IMT mm NS NS Metoprolol Carvedilol NS Marfella et al, Am J Hypertens 2005: 18: 308 < <0.02

48 CYT006-AngQb, a Vaccine Against Hypertension Targeting Angiotensin II Lancet 2008;371:

49 Change of Daytime BP (week 14 vs. Baseline) Lancet 2008;371:

50 24hr BP Profile at Week 14 Lancet 2008;371:

51 Change of Early Morning BP (week 14 vs. Baseline. 300µg CYT006-AngQb) DBP SBP Usefulness of RAAS-inhibitory action, &/or of long T1/2 in controlling Morning HTN Lancet 2008;371:

52 Summary (I) There is a pronounced diurnal rhythm of BP and CV events, with a peak of both in the morning hours, and a decrease during the night. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. With some antihypertensive drugs the time of dosing time of dosing may have significant effects on the diurnal pattern of BP.

53 Summary (II) Inhibition of SNS or RAAS may be useful for controlling MBPS Different antihypertensive drugs may have different effects on the morning surge of BP.

54 Conclusions Morning BP surge is an independent risk for advancing the atherosclerosis process, TOD and triggering CV events. In addition to strict BP control, antihypertensive therapy targeting MBPS could achieve more beneficial effect for prevention of CV disease in high-risk hypertensive patients.

55 KOALA Symposium

56 Thank you for your attention!

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59 Factors Influencing Morning Surge Brain Aging Clock gene Stress Sympathetic system Renin-angiotensin system HPA axis Nitric oxides Cold temp Morning BP

60 Factors Influencing Exaggerated Morning Surge Age (>70 yr) African-AmericanAmerican Ethnicity Day of week (Mon) / Season of year (Winter) Tobacco / Alcohol use Sodium / Caffeine / Medication (e.g. oral contraceptives)

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62 Controlled onset extended release Verapamil vs. Atenolol l or Hydrochlorthiazide n=8241 3yr f/u JAMA 2003;289:

63 Reducing target-organ damage Reduced blood pressure slows the rate of GFR decline Mean arterial pressure (mmhg) De ecline in GFR (ml/m min/year) /85 140/90 r = 0.69; P < 0.05 Untreated hypertension -14 Bakris et al. Am J Kidney Dis 2000;36:

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65 Morning BP Surge &CVE Events

66 Target-organ Damage Increases Cardiovascular Endothelial dysfunction Risk Endothelium plays akey role in controlling peripheral arteriolar resistance Endothelial dysfunction can be observed as an inapropriate vasodilators/vasoconstrictors response Nitric oxide is a key endogenous vasodilator It is one of the earliest markers for target- organ damage Klahr, Morrissey. Kidney Int Suppl 2000;75:S7 S14 It contributes to cardiovascular disorders to

67 Target-organ Damage Precedes Clinical Events Risk factors: diabetes, obesity, smoking, age Apoptosis LVH Fibrosis Arrhythmia Heart failure MI Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Hypertension Thrombosis Vascular disease Stroke Cognitive dysfunction Death Decreased GFR Proteinuria/albuminuria Glomerulosclerosis Renal failure

68 Target-organ Damage Increases Cardiovascular Risk Left ventricular hypertrophy ncidence ts) djusted in 00 patient ear age-ad (per 10 2-ye Hypertension Hypertension + LVH 0 Stroke Heart failure Coronary disease Kannel. Eur Heart J 1992;13 (Suppl D):82 88

69 Target-organ Damage Increases Cardiovascular Risk Carotid IMT Daniel HO et al. NEJM 1997;340:14 22

70 Target-organ Damage Increases CV Risk * Incidence e of cardiova ascular even nts (% of patients per year) Albuminuria (in type 2 diabetes) * Normoalbuminuria Microalbuminuria Macroproteinuria *P< versus normoalbuminuria after adjusting for other risk markers Gimeno Orna et al. Rev Clin Esp 2003;203:

71 Lowering BP reduces CV risk Meta-analysis of 61 prospective, observational studies One million adults, 12.7 million person-years 2 mmhg decrease in mean SBP 7% reduction in risk of ischaemic heart disease mortality 10% reduction in risk of stroke mortality Lewington et al. Lancet. 2002;360:

72 Characteristics of Morning BP Reactivity Subgroup < < < Am J Hypertens 2005;18:

73 24h Profiles of SBP & SBP Variation Normo HTN Hypertension. 2005;45:

74 Rate of SBP Variation During Morning BP Surge Correlated Independently to Larger CCA-IMT Hypertension. 2005;45:

75 A significant increase in physical and mental activity adjusted i adjusted d ischemic i time at the hour of awakening Circulation. 1996;93:

76 Telmisartan compared with Perindopril last 8 hours 100 P< h mean Telmisartan versus Perindopril Pretreatment 95 DBP (mm mhg) Telmisartan 80 mg Perindopril il 4 mg P 0.05 Telmisartan versus Perindopril Post-treatment Double-blind Nalbantgil et al. Int J Clin Pract 2004;58:50 54 Time of day (hours) comparative study

77 Diuretics Convert Non- Dippers to Dippers Systolic pressure mmhg Day Night Uzu & Kimura Circ 1999; 100:1635 No Rx HCTZ No Rx HCTZ Dippers Non-Dippers

78 Telmisartan vs Amlodipine using 24-h ABPM BP (mm Hg) 160 Week 12, SBP Placebo (n=58) Telmisartan ( mg) (n=62) Amlodipine (5-10 mg) (n=65) Time Lacourcière Y et al, in press

79 Relevance of trough:peak ratios to 24-h BP control 180 Placebo Blood pressure e (mmhg ) 160 Drug A 140 (T:P ratio =75%) Peak 120 Drug B 100 (T:P ratio =45%) Dose Dose Trough 07:00 11:00 15:00 19:00 23:00 03:00 07:00 Time of day Ellioit, Meredith. J Hypertension 1995;13:

80 Diuretics Convert Non- Dippers to Dippers 150 Systolic pressure mmhg Day Night No Rx HCTZ No Rx HCTZ Dippers Non-Dippers Uzu & Kimura Circ 1999; 100:1635

81 Circadian Change

82 Adverse Events of CYT006-AngQb Placebo 100μg 300μg p (n=24) (n=24) (n=24) Injection-site 16 (66.7%) 23 (95.8%) 19 (79.2%) induration Injection-site 8 (33.3%) 3%) 18 (75.0%) 21 (87.5%) edema 3 Headache 8 (33.3%) 3%) 6 (25.0%) 15 (62.5%)