2. Clinical Significance of an Exaggerated Blood Pressure Response During Exercise ANDREAS PITTARAS MD

3. Patient A Patient B Age 67 58 Rest BP 120/80 120/78 BP @ 5 METs 160/80 220/90 Peak BP 190/80 230/100

4. QUESTIONS The Clinical Significance? What to do about it?

5. Definition Peak Exercise SBP >210 mm Hg for men and 190 mm Hg for women respectively (Framingham) SBP >200 mm Hg at Exercise Workload of about 6-7 METs

6. Exaggerated BP Response to Exercise and Associations Future Development of HTN Cardiovascular Mortality and Cardiovascular events Left Ventricular Hypertrophy

7. Clinical Significance False-positive results were twice as likely in patients with hypertensive response to exercise echocardiography (22% vs 12%). Jong-Won Ha, et al. JACC 2002:112:161-66

8. Exaggerated BP and Future Development of Hypertension

9. New-onset of HTN and Exercise BP in Men (n=1026) The Framingham Heart Study Odds Ratio DBP SBP * * Singh JP, et al. Circulation 1999;99:1831-36

10. Exaggerated BP Response to Exercise and Risk for Developing HTN (n=1,033) Miyai, et al. Hypertension 2002;39:761-6 DBP SBP 4.7 yrs F/U Relative Risk

11. Exaggerated BP Response to Exercise and Risk for Developing HTN Miyai, et al. Hypertension 2002;39:761-6 Relative Risk

12. Exaggerated Exercise BP and Future HTN (Conclusion) Overall, an exaggerated BP response to exercise is likely to lead to future HTN Confounding factors such as age, gender, and physical fitness have not always been considered Pre-hypertension ?

13. Patients with Pre-hypertension are at twice the risk to develop hypertension compared to those with lower BP values. Vasan RS, et al. The Framingham Study. JAMA 2002;287:1003-1010

14. Exaggerated BP and CV Events and CV Mortality

15. Exercise BP and CV Mortality in Middle-aged Men (n=1999) % <140 / <200 mm Hg >140 / >200 mm Hg 200 mm Hg >140 / <200 mm Hg Mundal et al. Hypertension 1994;24:56-62 * RR=2.0 NS F/U: 16 yrs

16. Exercise BP and Risk of Developing MI in Middle-aged Men (n=1999) % * <140 / <200 mm Hg >140 / <200 mm Hg >140 / >200 mm Hg 200 mm Hg Mundal et al. 1996; Hypertension;27:324-29

17. Conclusion SBP >200 mm Hg at exercise intensity of about 6 METs is a stronger predictor of CV and MI morbidity and mortality than resting BP In pts with resting HTN. Mundal R. et al., Hypertension 1996;27(1):324-29

18. Exaggerated BP Response and Left Ventricular Hypertrophy

19. Resting BP is weakly related to LVH (r=0.26) and can only partially explain its development and progression.

20. Exaggerated BP & LVH in Normotensive Men An exaggerated blood pressure (SBP >210) at peak exercise is associated with left ventricular hypertrophy (LVH). The association is much stronger than that between resting BP and LVH. Gottdiener JS., et al. Annals of Internal Medicine 1990; 112:116-66

21. Peak Exercise SBP and LV MASS HTN with SBP >210 mm Hg <210 mm Hg Polonia J, et al. Eur Heart Journal 1992; 13(A):30-36 g/m2 >210 mm Hg

22. Peak Exercise BP and LV MASS <210 mm Hg Molina L, et al. Am J Cardiol 1999; 84:890-93 >210 mm Hg

23. Peak Exercise BP (SBP>210 mm Hg) and LVH in Men & Women <210 mm Hg >210 mm Hg Lauer et al. Annals Intern Med 1992;116;203-10 g/m2

24. Conclusion The relationship between Peak exercise BP and LVM is confounded by a number of baseline variables so that its biological significance must be questioned. Lauer et al. Annals Intern Med 1992;116;203-10

25. Peak vs Sub-maximal Exercise BP Peak Exercise BP –Relatively difficult to assess –Impractical –Based on a relative workload Exer. BP (5-7 METs) –Easier to assess –Practical (reflects daily activities) –Wider clinical application –Based on absolute workloads

26. Exercise SBP and Fitness in Normotensive Men (n=1,025) * * p<0.01 mm Hg Low-Fit Moderate High-Fit * *

27. Patients with Pre-hypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg), are at twice the risk to develop hypertension compared to those with lower BP values. Vasan RS, et al. The Framingham Study. JAMA 2002;287:1003-1010

28. LVMI Predictors for Pre-HTNsive Men (Multiple Regression) M (n=269) W (n=243) R 2 R 2 SBP @ 7 METs 0.62 0.50 Age 0.64 0.51 T-Time 0.65 0.53

29. LVMI & Exercise SBP Association in Pre-Hypertensive Women Kokkinos P, Pittaras A et al. Circulation 2004 SBP>169 mm Hg

30. LVMI & Exercise SBP Association in Pre-Hypertensive Men Kokkinos P., Pittaras A et al. Circulation 2004 SBP>164 mm Hg

31. LVMI & Exercise SBP in Pre-hypertensive Men and Women * * p<0.01 Normal EX-HTN * Kokkinos P., Pittaras A et al. Circulation 2004 g/m2

32. Prevalence of LVH in Pre-HTN Men % OR CI p-value –EX-HTN (+): 59 30.2 13.8-66.2 0.00 –EX-HTN (-) : 4.5 –RR= 5.9 times higher likelihood of LVH/10 mm Hg Increase in SBP@ 6 min. of exercise Women –EX-HTN (+): 86 21.6 12.3-38.2 0.00 –EX-HTN (-) : 22 –RR= 2.9 times higher likelihood of LVH/10 mm Hg increase in SBP@ 6 min. of exercise

33. Conclusions Systolic BP at about 6-7 METs is the strongest predictor of LV mass in Pre- hypertensive men and women. The threshold for LVH is SBP >164 mm Hg for men and >169mm Hg for Women. The likelihood of having LVH increases by 6-fold in men and 3-fold in women for every 10 mm Hg increase in SBP above these thresholds.

34. What to Do for Patients with Exaggerated BP Response to Exercise ? Antihypertensive Agents Exercise Training

35. Exercise BP and Antihypertensive Meds (n=1,977) * * * p<0.01 BB-Based Others * * mm Hg

36. Exercise BP and Antihypertensive Agents (n=1,977) * p<0.01 BB-Based ACE CCB Diuretics mm Hg

37. Clinical Significance Beta-blockade may be a prudent approach to protect against excessive and repetitive elevations in BP likely to occur during vigorous activities such snow-shoveling basketball, tennis, etc., that require repetitive burst of effort to maximal or near maximal levels.

38. What to Do for Patients with Exaggerated BP Response to Exercise ? Antihypertensive Meds Exercise Training

39. Exercise Indices for Fit and Unfit Women Normotensive Fit (n= 557) Unfit (n=463) SBP- 6 min 145±18 156±20 * HR- 6 min 136±15 152±17 * Hypertensive Fit (n= 99) Unfit (n=186) SBP- 6 min 172±21 184±21 * HR- 6 min 141±15 156±15 * Kokkinos P. Pittaras A et al, J Cardiopulmonary Rehab 2002;22:178-183 * p =0.000

40. Exercise BP, Fitness & LVMI in Men * * * p<0.01 Pittaras A, et al. Circulation 2003 Low-Fit Moderate High-Fit

41. Exercise BP, Fitness & LVMI in Women * * * p<0.01 Pittaras A, et al. Circulation 2003 Low-Fit Moderate High-Fit

42. SBP Following Aerobic Training * * * *p<0.01 * Kokkinos P. et al, Am J Cardiol. 1997 mm Hg

43. Wall Thickness at Baseline and 16 wks mm Kokkinos, Pittaras A et al. New Engl J Med 1995;333:1462-7 * * * p<0.05

44. LVMI at Baseline and 16 Wks of Exercise Kokkinos, Pittaras A et al. New Engl J Med 1995;333:1462- 7 * * p<0.05 Baseline 16 weeks g/m2

45. Antihypertensive Agents and Exercise

46. Exercise SBP and Fitness in Hypertensive Men on B-Blockers (n=453) * * p<0.01 mm Hg Low-Fit Moderate High-Fit * *

47. Exercise SBP and Fitness in Hypertensive Men on Meds (n=455) * * p<0.01 mm Hg Low-Fit Moderate High-Fit * *

48. Does exercise BP at 5-7 METs reflect daytime Ambulatory BP?

49. Exercise BP & ABP in Fit & Unfit Men EX-BP ABPM LVMI EX-BP ABPM

50. Exercise BP & ABP in Fit & Unfit Women EX-BP ABPM LVMI EX-BP ABPM

51. Summary and Conlusions Fit individuals have Lower: BP at intensities of 5-7 METs Lower ABPM Lower LVMI Than Unfit. Physical activity lowers the daily hymodymanic load, leading to lower LV Mass.

52. Mitigates the hemodynamic load During Daily Activities Prevents or Attenuates Increases in LV Mass

53. How Much Physical Activity? Some is Better than None! Choose an activity you enjoy Start Low & Progress Slowly Start as low as 10 min/week Split duration (AM/PM) if needed Increase duration by 1-2 min/wk Goal: 100-200 minutes/week Be Consistent (2-6 times/week)

54. How Much Physical Activity ? Think F.I.T F- Frequency: 2-6 days/Wk I – Intensity : 60-80% of HRR T- Time :100-200 min/week

55. The daily hemodynamic load is likely the impetus for the development and progression of LVH. SBP at 5-7 METs of exercise reflects the hemodynamic load during daily activities.

56. Therefore, attenuating an abnormal rise in BP during daily physical exertion may prevent the development and/or maintenance of LVH.

57. Conclusion 1 High fit Women had: Lower LVMI BP @ 6 min of Exercise

58. The metabolic demand of about 6-7 METs at 6 min of exercise (Bruce protocol) is equivalent to that of most daily activities. Thus, the 6-minute exercise BP may reflect the hemodynamic load during daily activities.

59. Furthermore, the maintenance and progression of LVH may be mediated by this daily hemodynamic load. Thus, attenuating an abnormal rise in BP during daily physical exertion may prevent the development and/or maintenance of LVH.

60. Correlation of 6-minute Exercise SBP, LVMI and Daytime ABP in Men SBP@ 6-min ABPM LVMI r=0.73 r=0.81 r=0.68

61. Correlation of 6-minute Exercise SBP, LVMI and Daytime ABP in Women SBP@ 6-min ABPM LVMI r=0.79 r=0.71 r=0.67

62. Peak Exercise DBP Before and After Exercise Training in Women Seals et al, Am J Cardiol ‘97 mm Hg P<0.05

63. Peak Exercise SBP Before and After Exercise Training in Women Seals et al, Am J Cardiol ‘97 mm Hg P<0.05

64. Exercise RPP at Pre & Post Training RPP * 1000 * * * *p<0.05 Kokkinos P. et al, Am J Cardiol. 1997

65. Exaggerated BP & False-Positive Exercise Test Results Jong-Won Ha, et al. JACC 2002:112:161-66 132 pts with Peak Exercise SBP>220 mm Hg for Men; > 190 mm Hg for Women 108 had positive exercise Echo finding 24/108 (22%) had no significant CAD 416 pts with Normal Exercise BP 320 had Positive Exercise Echo Findings 39/320 (12%) had no significant CAD

66. Exercise Response for Pts on Beta- Blockers vs Other Antihypertensive Meds Variables Others (n=1254) BB (n=561) Δ SBP @ 3 min 167±27 151±26 16 SBP @ 6 min 182±27 164±25 18 Peak SBP 192±28 175±30 17 HR @ 3 min 119±17 106±17 13 HR @ 6 Min 133±16 119±18 14 Peak HR 148±17 31±21 17 Ex. Time (sec) 412±166 419±160 7 P<0.001

67. BP Response to HR During Exercise Test and Risk of Future Hypertension Miyai N, et al. Hypertension 2002;39761-66 N=1033 Men, No HTN, DM or CVD Cycle Ergometer; Automated BP monitoring device. Age: 42.9 ±8.5 yrs; range: 20-59 yrs 726 pts with complete data; 4.7 yrs F/U

68. Exercise BP Predicts CV Mortality in Middle-aged Men Mundal et al. 1994; Hypertension;24:56-62 N=1999 healthy men F/U: 16 yrs Exercise BP at 600 kg-m/min (~100 watts; approximately 6 METs)

69. Peak Exercise SBP and LV MASS HTN with SBP >210 mm Hg <210 mm Hg Polonia J, et al. Eur Heart Journal 1992; 13(A):30-36g/m2 >210 mm Hg

70. SBP at sub-maximal exercise reflects the daily hemodynamic load. Therefore, it may be a stronger predictor of HTN and LVH. Sub-maximal exercise BP may also have a wider clinical application than maximal exercise BP.

71. Left ventricular hypertrophy (LVH) is a powerful and independent predictor of cardiovascular events in patients with and without obstructive coronary disease. The risk for CV morbid events, including sudden cardiac death, increases-three fold in patients with LVH. Levy D., et al. N Engl J Med 1990;332:1561-66 Ghali JK et al., 1992; Ann Intern Med 1992;117:831-36 Koren MJ et al., 1991; Ann Intern Med 1991;114:345-52 Casale PN, et al., Ann Intern Med 1986;105:173-78

72. Clinical Characteristics Men Women N 269 243 Age 49±10 54±10 RHR 78 ± 8 82 ±14 RSBP 129 ±6 132 ±7 RDBP 76±7 79 ±8 BMI27±2.6 27±2.4 * p =0.008

73. Exercise SBP and Fitness in Hypertensive Men (n=908) * mm Hg B-Blockers Other Meds

74. LVMI in Normotensive and Hypertensive Women * * * p<0.01 Kokkinos, Pittaras A et al. Circulation ‘98 g/m2 Low-Fit Moderate High-Fit

75. Exercise BP, Fitness & LVMI in Men * * * p<0.01 Pittaras A, et al. Circulation 2003 EX-BP ABPM LVMI

76. SBP at 7 METs and LVMI in Fit & Unfit Normotensive Women * * * p<0.02 Kokkinos P. Pittaras A et al. JACC ‘99 SBP LVMI SBP *

77. SBP at 7 METs and LVMI in Fit & Unfit Hypertensive Women * * p<0.02 Kokkinos P. Pittaras A et al. JACC ‘99 Low-FitHigh-Fit * Low-Fit High-Fit

78. Exaggerated BP & LVH in Normotensive Men Normotensive Men (N=39) Age: 44.6±8.5 LVH (LVMI >134 g/m 2 ) found in 63% (14/22) of t hose with Peak Exercise SBP >210 mm Hg. Gottdiener J. et al. Annals Intern Med 1990:112:161-66

79. Correlations (r) of Sub-maximal Exercise SBP and ABP (n=892) 5-MET 7-MET r r Daytime0.710.78 Nighttime0.690.77 24-hours0.700.77

80. LVMI & Exercise SBP @ 7-METs in Pre-Hypertensive Women * p<0.01 Normal BP Ex-HTN * *

81. LVMI & Exercise SBP @ 7 METs in Pre-Hypertensive Men * p<0.01 Normal BP Ex-HTN * *