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Unraveling the Mysteries of Pre-hypertension

Unraveling the Mysteries of Pre-hypertension. Joel Neutel. MD Professor of Medicine University of California Irvine Director of Research Orange County Research Center. Family History of Hypertension. Neutel JM et al. Am Heart J 1992;124:435-440. 350. 2.5. 300. 2.0. 250. 1.5. 200.

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Unraveling the Mysteries of Pre-hypertension

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  1. Unraveling the Mysteries of Pre-hypertension Joel Neutel. MD Professor of Medicine University of California Irvine Director of Research Orange County Research Center

  2. Family History of Hypertension Neutel JM et al. Am Heart J 1992;124:435-440.

  3. 350 2.5 300 2.0 250 1.5 200 150 1.0 100 0.5 50 0 0.0 Neurohormonal Levels in Normotensive Patients With and Without a Family History of Hypertension 310 ± 17 2.1 ± 0.2 † 1.6 ± 0.2 * 190 ± 15 Plasma renin activity (ng/Ang I/mL/h) Norepinephrine (pg/mL) Family History No Family History Family History No Family History *p<0.01. †p<0.05. Neutel JM et al. Am Heart J. 1992;124:435-440.

  4. Plasma Insulin Levels and Insulin Sensitivity in Subjects with and without a Family History of Hypertension * * Plasma Insulin Insulin Sensitivity No Family History Family History No Family History Family History Neutel JM et al. Am Heart J. 1992;124:435-440. *P< 0.05

  5. Total Cholesterol and Triglyceride Levels in Subjects with and without a Family History of Hypertension * Cholesterol Levels Triglyceride Levels No Family History No Family History Family History Family History Neutel JM et al. Am Heart J. 1992;124:435-440. *P< 0.05

  6. 100 1.00 90 0.90 80 0.80 70 0.70 60 0.60 50 0.50 40 0.40 30 0.30 20 0.20 10 0.10 0 0 Left Ventricular Mass Index and Doppler Echocardio-graphic Characteristics in Normotensive Subjects With and Without a Family History of Hypertension 75 ± 17 0.64 ± 0.19 * 57 ± 13 † 0.46 ± 0.10 Left ventricular mass (g/m2) A/E ratio Family History No Family History Family History No Family History *p<0.05. †p<0.01. Celentano et al. J Hypertens. 1988;6(suppl 4):107. Graettinger WF et al. Am J Cardiol. 1991;68:51-56.

  7. 1.8 0.6 1.6 0.5 1.4 1.2 0.4 1.0 0.3 0.8 0.6 0.2 0.4 0.1 0.2 0.0 0.0 Proximal and Distal Compliance in Normotensive Subjects With and Without a Family History of Hypertension * 1.79 ± 0.38 1.56 ± 0.38 † 0.50 ± 0.021 0.34 ± 0.018 Proximal compliance (mL/mm Hg) Distal compliance (mL/mm Hg) Family History No Family History Family History No Family History *p<0.05. †p<0.01.

  8. 3.2 125 3.0 120 115 2.8 110 2.6 105 2.4 100 2.2 95 2.0 90 0 0 Family History of Hypertension Creatinine clearance (mL/min) Albumin excretion ratio (µg/min) * Positive Negative Positive Negative *p<0.01.

  9. WCH in Patients with and without a Family of Hypertension ** WCH (%) Blood Pressure (mm Hg) No Family History Family History No Family History Family History Neutel J et al., Am Heart J 1992;124:435-448. ** P < 0.01

  10. Characteristics of Normotensives and HypertensivesWith and Without a Family History of Hypertension BMI = body mass index

  11. Plasma Norepinephrine and Plasma Renin Activity **p<0.02 *p<0.05 HT = hypertensive; NT = normotensive Neutel J et al., Am Heart J 1992;124:435-448. **p<0.02 *p<0.07

  12. Total Cholesterol Levels in Patients with and without a Family History of Hypertension ** * ** **p<0.002 *p<0.04 HT = hypertensive; NT = normotensive Neutel J et al., Am Heart J 1992;124:435-448.

  13. Insulin Sensitivity and Plasma Insulin Levels **p<0.01 *p<0.02 **p<0.01 *p<0.03 HT = hypertensive; NT = normotensive Neutel J et al., Am Heart J 1992;124:435-448.

  14. Distal Compliance (C2) in Patients with and without a Family History of Hypertension * ** ** Distal Compliance **p<0.01 *p<0.04 HT = hypertensive; NT = normotensive Neutel J et al., Am Heart J 1992;124:435-448.

  15. Changes in Proximal and Reflective Compliance ** * ** NS *p<0.05 **p<0.01 Neutel JM Am J Cardiol 2006

  16. Endothelial Dysfunction Leads to High Blood Pressure and Atherosclerotic Disease NO Ang II Hyperinsulinemia Family History Norepinephrine LDL-cholesterol Smoking Dysfunction Lipid deposition and Inflammatory-cell infiltrate Collagen and Fibronectin deposition SMC migration And growth clotting Vasoconstriction Potentiates Potentiates Atherosclerosis CVD High Blood Pressure Neutel J. 2001

  17. Changes in Endothelial Function Normal Endothelium Dysfunctional Endothelium NO AII AII AII NO AII AII AII

  18. Patients with Strokes And Heart Attacks (%) Patients with LV Heart Renin Activity Enlargement (%) Total Strokes Attacks 12 (20) 18 (15) 8 (22) 0 14 (11) 5 (14) 0 6 (5) 2 (6) 0 8 (6) 4 (11) Low Normal High Brunner et al N Eng J Med 1972 ;286: 441

  19. Hypertension, Oxidative Stress, Angiotensin II: At the Source of Vascular Damage Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.

  20. Normal endothelium Dysfunctional endothelium AII AII NO NO NO NO NO AII AII AII ACEi Monocytes Thrombus Platelets Adapted from Gibbons G. Am J Cardiol, 1997;79, 3-8 Regulation of ACEi and NO in Endothelial Dysfunction and Atherosclerotic DiseaseACEi Therapy Lipid-laden macrophage

  21. 12 16 14 10 High normal 12 8 10 Normal Cumulative incidence (%) 8 6 6 Optimal 4 4 2 2 0 0 12 12 0 0 2 2 4 4 6 6 8 8 10 10 Time (y) Time (y) Impact of High Normal BP on CV Disease Risk in Men and Women WOMEN High normal (140/90) Cumulative incidence (%) Prehypertension Normal (130/85) Normal Optimal (120/80) (120/80) MEN Optimal BP: <120/80 mm Hg; normal BP: 120-129/80-84 mm Hg; high normal: 130-139/85-89 mm Hg. Vasan RS. N Engl J Med. 2001;345:1291-1297.

  22. MRFIT: Systolic BP And CHD Mortality Risk Pyramid For Men SBP (mm Hg) % of Total CHD Deaths Pop. % RR >180 7.2 0.9 170-179 6.8 1.2 160-169 10.1 2.7 150-159 19.5 6.2 140-149 23.4 12.8 130-139 20.7 22.8 120-129 9.9 28.4 110-119 1.3 19.0 <110 0.0 6.1 Stage 2 24.5 4.6 107 Stage 1 42.9 19.0 51 Pre-HTN 30.6 53.2 11 Normal 1.3 25.1 1 Adapted from Stamler et al. Arch Intern Med 1993;153:596.

  23. JNC 7 Re-Classification of SBP/DBP JNC 7 (2003) JNC VI (1997) Hypertension JNC VI. Arch Intern Med. 1997;157:2413-2446. JNC 7. JAMA, May 21, 2003-Vol 289, No.19, 2560-2572.

  24. TROPHY Background and Objectives • Background • 45 million people in the US have prehypertension, a condition associated with excess cardiovascular risk • Arteriolar hypertrophy and endothelial dysfunction contribute to the self-acceleration of this disease. Early treatment might delay or prevent the development of hypertension Objectives • Determine whether treatment with an ARB in subjects with prehypertension will: • suppress clinical hypertension during the active treatment • delay the onset of clinical hypertension after discontinuation of active treatment Julius, Stevo, et. al. JAMA 2006; 354:1-13

  25. Study Design

  26. TROPHYStudy Design 772 subjects, age > 30 or < 65, never treated for HTN, first visit BP < 160/100, avg automated BP over 3 visits < 135/85-89 or 130-139 < 89 lifestyle counseling throughout the trial Candesartan 16 mg qd x 2 years (n = 391) Placebo x 2 years (n = 381) Placebo x 2 years • Primary Study Endpoints: • BP > 140 mmHg systolic and / or > 90 mmHg diastolic at any 3 visits • BP > 160 mmHg systolic and / or > 100 mmHg diastolic at any visit • BP > 140 mmHg systolic and / or > 90 mm Hg diastolic at last study visit • In clinical investigator’s judgment pharmacologic therapy is indicated (target organ damage or other reasons) Julius, Stevo, et. al. JAMA 2006; 354:1-13

  27. TROPHY STUDYBP Inclusion Criteria SBP 130 – 139 mm Hg and DBP < 89 mm Hg OR SBP < 139 mm Hg and DBP 85 – 89 mm Hg Julius S. N Engl J Med 2006;354:1-13

  28. TROPHY STUDYBaseline Characteristics Julius S. N Engl J Med 2006;354:1-13

  29. TROPHY STUDYBaseline Characteristics (cont) Julius S. N Engl J Med 2006;354:1-13

  30. TROPHY STUDYNew Onset Hypertension 2 years 4 years Number of patients Number of patients * * (placebo) * P<0.001 * P<0.007 Julius S. N Engl J Med 2006;354:1-13

  31. TROPHY STUDY Kaplan-Meier Analysis of New-Onset Clinical Hypertension

  32. Pre-hypertension SBP 120-139 mmHg or DBP 80-89 mmHg 25 Million Americans have Pre-hypertension How should this be managed • Encourage Lifestyle Modifications • Without compelling indication – no treatment • With compelling indication – Drug(s) for compelling indication JNC 7. JAMA. 2003;289(19):2560-2574

  33. Bothrops jararaca 9

  34. ACE Inhibitors • An ACE inhibitor was first discovered in snake venom of Bothrops jararaca, a Brazilian viper • Identified as a nonapeptide named teprotide • Also known as bradykinin potentiating peptide 9 alpha or BBP9 alpha • Sequence: Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro or PyrWPRPQIPP 8

  35. Proline

  36. ACE Inhibitors • Captopril – first commercial ACE inhibitor. 10

  37. Lactotripeptides Clinical trials in Japan demonstrated that Lactobacillus helveticus and Saccharomyces cerevisiaefermented milk produced two tripeptides ile-pro-pro (IPP) and val-pro-pro (VPP). These tripeptides are well absorbed from the GI tract when given orally 15

  38. Lactotripeptides Both IPP and VPP possess ACE inhibitory activity as determined by the inhibition of the metabolism of the test peptide Hip-His-Leu 15

  39. Antihypertensive effects of VPP and IPP on spontaneously hypertensive rats 10 0 ＊ -10 ＊ Changes of SBP (mm Hg) -20 * ** * ** P < 0.05 ** ** ** -30 P < 0.01 *** *** P < 0.001 -40 ＊ Mean ± SE -50 0 2 4 6 8 10 24 Time after administration (h) Ile-Pro-Pro (0.3mg/kg) Control Val-Pro-Pro (0.6mg/kg) Fermented Milk (5ml/kg) (Nakamura et al., J. Dairy Sci. 1995)

  40. Lactotripeptides • AmealPeptide (VPP and IPP) has undergone the most extensive human clinical and toxicity testing (14 published, randomized, clinically controlled trials). • No adverse reactions, including cough, have been reported. AmealPeptide not involved in cytochrome P450-mediated interactions with other drugs • AmealPeptide exists in two forms: a fermented milk drink (milk is fermented with Lactobacillus helviticus) and in pill form (derived by digesting milk casein with a protease from Aspergillus oryzae). • Both the food drink, marketed in Japan as a FOSHU product, and the pill, marketed in the U.S. as a dietary supplement (with GRAS recognition from the US FDA), are efficacious in lowering BP. 36

  41. Effect of VPP and IPP on the Conversion of Angiotensin I to Angiotensin II, and the Bradykinin Production in Aorta of Spontaneously Hypertensive Rats Figure 3. Levels of Angiotensin I, Angiotensin II and Bradykinin in aorta were analyzed using Sep-pak tC18. The peptides in the eluted materials were measured with commercially available Enzyme Immunoassay kits.

  42. Effects of LTP’s on Pre-hypertensive Subjects (SBP:120-139mmHg) mmHg) 150 　 ：　Placebo (n=53) 　 ：　Treatment (n=53) 140 SBP 130 * * * * 120 Mean + SD *P< 0.05 110 Blood pressure (mmHg) 100 90 DBP 80 * * * 70 60 -4 -2 0 2 4 6 8 10 12 14 16 Time (Week) Nakamura et al. (J. Nutr. Food, 7:123-137, 2004)

  43. Effects of LTP’s on Pre-hypertensive Subjects (SBP:120-139 mmHg) 150 : Placebo (n=20) : Treatment (n=20) Systolic BP 140 Mean + SD Blood pressure (mmHg) *P< 0.05 130 * * * * * * Diastolic BP 90 80 * * * 70 -2 0 2 4 6 8 10 12 14 16 Time (Week) (Sano et al., J. Medical Food)

  44. Effects of LTP’s on BP in Treated Hypertensive Patients Systolic Blood Pressure 5 0 Placebo (n=13) (SBP:150.9±9.5, DBP:87.0±9.1 ) -5 ΔBP (mmHg) Treatment (n=17) 2.6 mg of LTP/100 g fermented milk (SBP:158.5±11.1, DBP:88.7±9.4 ) -10 -15 * * * -20 0 4 8 12 Diastolic Blood Pressure 5 Drugs used Active Placebo Calcium antagonist 11 9 ß-Blocker 3 4 ACE inhibitor 2 3 Diuretics 4 0 Others 3 3 None 1 3 0 ΔBP (mmHg) -5 -10 * * -15 12 0 4 8 (Week) Mean + SD (Hata et al., Am. J. Clin. Nutr.1996) *P< 0.05

  45. Effects of LTP’s on Stage-1 Hypertensive patients (SBP : 140-159 mmHg) 　 ： Placebo (n=33) 　 ： Treatment (n=31) 160 SBP 140 * Mean + SD * * * * 120 *P< 0.01 Blood pressure (mmHg) 100 80 * * * * * -2 0 2 4 6 8 10 12 Time (Week) Kajimoto et al, (J. Nutr. Food, 5: 55-66, 2002)

  46. 2-3: Stratified Analysis of 8 Clinical Trials by Start Value of Blood Pressure (Post-hoc analysis; 606 subjects from 8 studies) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) 149～140 ～160 159～150 139～130 ～100 99～95 94～90 89～85 10.0 0.0 -10.0 * * * -20.0 * * * * Treatment Mean + SD -30.0 * p<0.05 Placebo (3.4-5.4mg/day for 6-12 wks)

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