hypertension and cardiovascular disease

1. Hypertension and Cardiovascular Disease Cardiology Organ System December 7, 2005 Paul N. Hopkins, M.D., M.S.P.H. Cardiovascular Genetics University of Utah

7. Classification of blood pressure Definitions Measurement

8. HypertensionAn Historical Perspective Traube (Berlin, 1856) - High BP Is �Essential� Thought required for blood to flow through thickened arteries. Believed needed for proper kidney function. Unchallenged for almost 80 years. Page (Cleveland, 1934) - High BP Is NOT Necessary Developed techniques to estimate renal blood flow in humans. Demonstrated that early antihypertensive measures were not detrimental to renal function. Radical sympathectomy without loss of renal function. Renal Disease in Hypertension: A Historical Perspective Talking Points: Outdated perceptions have given way to modern concepts of renal disease and the pivotal role of hypertension. To modern physicians, the development of antihypertensive measures was seriously hampered until the early 20th century by the misperceptions and influence of leaders in medicine such as Professor Traube in Berlin. During most of this time, syphilitic heart disease, rheumatic fever and bacterial endocarditis dominated cardiovascular medicine. Both uncertainty about, and indifference to, high blood pressure combined as powerful deterrents to the emergence of modern concepts of hypertension. The important roles in the history of hypertension played by Professor Traube (Berlin, 1856) and Dr. Irvine Page (Cleveland, 1934) are detailed on this slide. It has been remarkable how quickly the field of hypertension has developed once modern concepts emerged. � References: Traube L. Ueber den zusammenhang von herz und nierenkrankeiten. Berlin: Hisrchwald, 1856. Page IH. Effect on renal efficiency of lowering blood pressure in cases of essential hypertension and nephritis. J Clin Invest. 1934;13:909. �Renal Disease in Hypertension: A Historical Perspective Talking Points: Outdated perceptions have given way to modern concepts of renal disease and the pivotal role of hypertension. To modern physicians, the development of antihypertensive measures was seriously hampered until the early 20th century by the misperceptions and influence of leaders in medicine such as Professor Traube in Berlin. During most of this time, syphilitic heart disease, rheumatic fever and bacterial endocarditis dominated cardiovascular medicine. Both uncertainty about, and indifference to, high blood pressure combined as powerful deterrents to the emergence of modern concepts of hypertension. The important roles in the history of hypertension played by Professor Traube (Berlin, 1856) and Dr. Irvine Page (Cleveland, 1934) are detailed on this slide. It has been remarkable how quickly the field of hypertension has developed once modern concepts emerged. � References: Traube L. Ueber den zusammenhang von herz und nierenkrankeiten. Berlin: Hisrchwald, 1856. Page IH. Effect on renal efficiency of lowering blood pressure in cases of essential hypertension and nephritis. J Clin Invest. 1934;13:909. �

9. Blood Pressure Classification Based on the average of at least 4 properly taken seated measurements! Check both arms first and use the higher arm for each visit. 2+ readings taken at each of 2+ visits. Usually 1+ week apart. Not taking antihypertensive drugs and not acutely ill or in pain.

10. Classification of BP for Adults Age 18 Years and Older � JNC 7 Guidelines

11. Recommendations for Follow-up Based on Initial Set of BP Measurements for Adults

12. Inaccurate Diagnosis Too few measurements Average 2+ readings separated by 2 minutes. Too few visits 2+ visits over several weeks after initial screening. Physical or emotional stress Rest 5 minutes Refrain from talking (raises systolic 10 mm Hg) No smoking or caffeine in the last 30 minutes. Don�t count for classification if in pain.

13. Inaccurate Diagnosis Inappropriate cuff size Use correct cuff size. Bladder to encircle 80% of the arm. Adequate width. Deflation too fast Deflate 2 mm Hg per heart beat. �White coat hypertension� Consider ambulatory BP monitoring.

14. Why does cuff size matter?

15. Why does cuff size matter?

16. Epidemiology of blood pressure Prevalence Associated risks

17. U.S. BLOOD PRESSURE DISTRIBUTION, ADULTS Classification BP Level Prevalence (millions) Normal < 120/80 50% (90) Prehypertensive 120-139/80-89 21% (38) Hypertensive ? 140/90 29% (52)

18. Prevalence of Hypertension (%) Result From NHANES, 1999-2000

19. Prevalence of hypertension is increasing (NHANES surveys)

20. Lifetime risk of developing hypertension in Framingham

21. Age and baseline blood pressure predict progression to HTN

22. Global Mortality 2000: Impact of Hypertension and Other Health Risk Factors The Comparative Risk Assessment module of the World Health Organization (WHO)�s Global Burden of Disease 2000 study performed a systematic assessment of changes in population health that would result from modifying exposure to environmental and physiological health risk factors. The methodology used to determine the attributable mortality and attributable burden of disease due to each risk factor was a counterfactual analysis in which the contribution of 1 or a group of risk factors is estimated by comparing the current disease burden with the magnitude that would be expected in an alternative scenario characterized by a theoretical minimal exposure. In the case of high BP and cholesterol, the theoretical minimal exposures were levels of 115 mm Hg and 3.8 mmol/L, respectively. This analysis of the contribution of 26 selected risk factors to global disease burden found that high BP was the leading cause of mortality in both developing regions and developed regions of the world. The study looked at the impact of risk factors on mortality in high mortality, developing regions such as many countries in Africa and Southeast Asia, lower mortality, developing regions such as Latin America and countries in the Western Pacific, and developed regions including Europe, Japan, and North America. In high mortality, developing regions, the leading causes of death were reported to be childhood and maternal undernutrition, including being underweight. However, despite the large contribution of communicable, maternal, perinatal, and nutritional conditions and their underlying risk factors to disease burden in the high mortality, developing regions, the �industrialized� risks of high BP, tobacco, and blood cholesterol levels also resulted in significant loss of life in these regions. Across developed regions, high BP, tobacco use, alcohol, high cholesterol, and high body mass index (BMI) were reported to be consistently the leading causes of loss of life. The Comparative Risk Assessment module of the World Health Organization (WHO)�s Global Burden of Disease 2000 study performed a systematic assessment of changes in population health that would result from modifying exposure to environmental and physiological health risk factors. The methodology used to determine the attributable mortality and attributable burden of disease due to each risk factor was a counterfactual analysis in which the contribution of 1 or a group of risk factors is estimated by comparing the current disease burden with the magnitude that would be expected in an alternative scenario characterized by a theoretical minimal exposure. In the case of high BP and cholesterol, the theoretical minimal exposures were levels of 115 mm Hg and 3.8 mmol/L, respectively. This analysis of the contribution of 26 selected risk factors to global disease burden found that high BP was the leading cause of mortality in both developing regions and developed regions of the world. The study looked at the impact of risk factors on mortality in high mortality, developing regions such as many countries in Africa and Southeast Asia, lower mortality, developing regions such as Latin America and countries in the Western Pacific, and developed regions including Europe, Japan, and North America. In high mortality, developing regions, the leading causes of death were reported to be childhood and maternal undernutrition, including being underweight. However, despite the large contribution of communicable, maternal, perinatal, and nutritional conditions and their underlying risk factors to disease burden in the high mortality, developing regions, the �industrialized� risks of high BP, tobacco, and blood cholesterol levels also resulted in significant loss of life in these regions. Across developed regions, high BP, tobacco use, alcohol, high cholesterol, and high body mass index (BMI) were reported to be consistently the leading causes of loss of life.

23. HYPERTENSION AS A RISK FACTOR Relative risk of 2.0 � 4.0 for: - CHD - Renal failure - CHF - Atrial fibrillation - Stroke - Dementia - PAD - Mild cognitive impairment JAMA 1999; 281:438 JAMA 1996; 275:1571 NEJM 1996; 334;13

24. Blood Pressure and CHD - MRFIT

25. Blood Pressure and CHD - MRFIT

27. CARDIOVASCULAR RISK AND USUAL BP Log-linear CVD death risk from 115/75 185/115 ? 20/10 mm Hg 2X ? in CVD death ? 2/0 mm Hg 10% ? in stroke death 7% ? in CHD death

28. Effect of Systolic BP and Diastolic BP on CHD Mortality: MRFIT Screenees (N=316,099)

29. Blood Pressure and Risk of Hemorrhagic Stroke in 114,793 Korean Men

30. Consequences of Untreated Hypertension � Historical Data

31. Pathological consequences of high blood pressure Increased atherosclerosis Direct damage to arteries & arterioles Arteriosclerosis Arteriolosclerosis

33. Hemodynamics and Lesion-Prone Sites

34. How does hypertension promote atherosclerosis? If not by �turbulence� then how? Clue: atherosclerosis is not seen in the venous circulation. Must be related to pressure itself.

35. How Does Hypertension Promote Atherosclerosis?

36. Hypertension damages arteries and arterioles Stage 1 & 2 pressures ? HYPERTROPHY of media Can protect against breakdown of blood-brain barrier. Stage 2 for prolonged periods or Stage 3+ ? ARTERIOSCLEROSIS in arteries myointimal hyperplasia (proliferation of smooth muscle cells in the intima) in arteries - collagen replaces much of media, �splitting� of internal elastic membrane - makes older arteries stiff. May promote abdominal aortic aneurysm.

37. Hypertension damages arteries and arterioles Stage 2 for prolonged periods or Stage 3+ ? ARTERIOLOSCLEROSIS in arterioles myointimal hyperplasia (proliferation of smooth muscle cells in the intima) increase in collagen and glycoproteins, accumulation of lipid (some from increased insudation from plasma). CAN LEAD TO LUMEN COMPROMISE. Severe HTN ? endothelial barrier breakdown, plasma fluids and proteins enter arteriole wall causing vascular edema, fibrin is deposited ? fibrinoid change, and ultimately fibrinoid necrosis ? organ ischemia and / or vessel rupture.

38. Pathological Consequences of Hypertension (continued) Arteriolosclerosis by itself (without atherosclerosis!) can lead to: In kidney: glomerulosclerosis, nephrosclerosis, ? ischemia ? malignant hypertension. In brain: ischemic changes (lacunar infarcts), dementia, Charcot-Bouchard aneurysms ? cerebral hemorrhage. In eye: microvascular changes, eventual blindness. In heart: hypertensive heart disease, CHF.

39. What causes hypertension? Several mechanisms and control systems understood. Can only rarely determine cause in any individual.

40. What causes hypertension? Frank�s Formula (BP = CO x PVR) Analogous to Ohm�s Law (flow = driving force / resistance) True by definition but provides little insight. Guyton Model Systems analysis approach based on years of careful empirical research (primarily in dogs).

41. Short-Term Pressure Natriuresis in Dogs

46. Decreased number of nephrons may cause hypertension

47. Decreased number of nephrons may cause hypertension

48. Rare Genetic Causes of Hypertension and Hypotension Hypertension Glucocorticoid Remediable Aldosteronism (GRA) dominant Liddle�s Syndrome dominant Apparent Mineralocorticoid Excess (11 �-hydroxysteroid dehydrogenase deficiency) recessive Others Hypotension Bartter syndrome Others

49. Common Gene Variants and Essential Hypertension Angiotensinogen (AGT) Linkage and association studies 235T (-6A) higher risk than 235M (-6G) Transgenic animal studies Local renal expression Human mechanistic studies a-Adducin G-protein �3 subunit Others

50. Secondary Hypertension (about 5% of all hypertension) Renal Failure Renovascular Hypertension Hyperaldosteronism Pheochromocytoma Polycystic kidney disease Oral Contraceptives Sleep Apnea (some consider a risk factor for primary hypertension).

51. Renal Stenosis

52. Take Home Messages from Hypertension Mechanisms Hypertension etiology is exceedingly complex. The kidney provides the dominant mechanism for long-term blood pressure control. All monogenic forms of hypertension (and low blood pressure) identified affect renal sodium handling. Drug mechanisms of action may be more complex than usually presented. Treatment is largely empirical and evidence-based.

53. Treatment of Hypertension Lifestyle interventions Drugs Intervention trials

54. Lifestyle Modification � The Foundation of Treatment Weight reduction most effective non-drug intervention Reduced salt diet ~50% of hypertensives are salt sensitive Exercise Must be regular � 5+ days/week, aerobic DASH 8 servings of fruits and vegetables each day Low fat dairy products Alcohol reduction

55. Central Fat Accumulation Predicts Incidence of Hypertension in the Framingham Study

56. LIFESTYLE MODIFICATION TO REDUCE BP

57. Pharmacologic Treatment Drug therapy will be covered in more detail in pharmacology lecture(s)� Coexisting conditions that influence antihypertensive choice: Congestive heart failure � ACEI, ARB, thiazides, aldosterone inhibitor, some beta-blockers Diabetes/renal disease � ACEI, ARB Angina � beta-blockers, calcium channel blockers Post-MI � beta-blocker Urinary retention, BPH � alpha-blockers Migraine headaches � some beta-blockers, calcium channel blockers, ACEIs, ARBs

58. Pharmacologic Treatment Numerous randomized controlled trials demonstrate CVD risk reduction with a variety of antihypertensive agents. Protects against stroke, coronary events, heart failure, progression of renal disease, progression to more severe hypertension, and all-cause mortality.

59. VA Cooperative Study in Male Patients with Diastolic BP 115-129 mm Hg

60. Blood pressure reduction appears to be most important factor in reducing CAD and stroke.

61. Diuretics and ?-Blockers as First-Line Treatment in Older Patients: Meta-Analysis of 10 Trials (N=16,164)

62. Blood Pressure Lowering Treatment Trialists� Collaboration Contributing Trials Blood Pressure Lowering Treatment Trialists� Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527-1535. Blood Pressure Lowering Treatment Trialists� Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527-1535.

63. Results of Prospectively Designed Randomized Blood Pressure-Lowering Trials The Blood Pressure Lowering Treatment Trialists� Collaboration performed 7 sets of prospectively designed overviews with data from 29 randomized trials (n=162,341). Inclusion criteria were random allocation of patients to either a blood pressure-lowering drug or placebo; random allocation of patients to different blood pressure goals; or random allocation of patients to regimens based on different classes of blood pressure-lowering drugs. In this figure, the weighted mean blood pressure differences between randomized groups appeared to be directly associated with differences in risks of stroke and CHD. According to the findings, greater risk reductions were produced by regimens that targeted lower blood pressure goals. Treatment with any commonly used regimen reduced the risk of total major CV events, and larger reductions in blood pressure produced larger reductions in risk.The Blood Pressure Lowering Treatment Trialists� Collaboration performed 7 sets of prospectively designed overviews with data from 29 randomized trials (n=162,341). Inclusion criteria were random allocation of patients to either a blood pressure-lowering drug or placebo; random allocation of patients to different blood pressure goals; or random allocation of patients to regimens based on different classes of blood pressure-lowering drugs. In this figure, the weighted mean blood pressure differences between randomized groups appeared to be directly associated with differences in risks of stroke and CHD. According to the findings, greater risk reductions were produced by regimens that targeted lower blood pressure goals. Treatment with any commonly used regimen reduced the risk of total major CV events, and larger reductions in blood pressure produced larger reductions in risk.

64. Results of Prospectively Designed Randomized Blood Pressure-Lowering Trials This figure, which also is taken from the Blood Pressure Lowering Treatment Trialists� Collaboration, compares blood pressure-lowering regimens based on different drug classes. The investigators pointed out that �although modest independent effects of specific drug classes on stroke or risk of coronary heart disease are not precluded by our findings, the results do suggest that blood pressure lowering is a major component of the benefit conferred by the regimens investigated. Direct evidence is provided by the regimens targeting different blood pressure goals (with various drug classes), which showed larger reductions in stroke and total major cardiovascular events from regimens targeting lower blood pressure goals.� This figure, which also is taken from the Blood Pressure Lowering Treatment Trialists� Collaboration, compares blood pressure-lowering regimens based on different drug classes. The investigators pointed out that �although modest independent effects of specific drug classes on stroke or risk of coronary heart disease are not precluded by our findings, the results do suggest that blood pressure lowering is a major component of the benefit conferred by the regimens investigated. Direct evidence is provided by the regimens targeting different blood pressure goals (with various drug classes), which showed larger reductions in stroke and total major cardiovascular events from regimens targeting lower blood pressure goals.�

65. Results of Prospectively Designed Randomized Blood Pressure-Lowering Trials This figure, which also is taken from the Blood Pressure Lowering Treatment Trialists� Collaboration, compares blood pressure-lowering regimens based on different drug classes. The investigators pointed out that �although modest independent effects of specific drug classes on stroke or risk of coronary heart disease are not precluded by our findings, the results do suggest that blood pressure lowering is a major component of the benefit conferred by the regimens investigated. Direct evidence is provided by the regimens targeting different blood pressure goals (with various drug classes), which showed larger reductions in stroke and total major cardiovascular events from regimens targeting lower blood pressure goals.� This figure, which also is taken from the Blood Pressure Lowering Treatment Trialists� Collaboration, compares blood pressure-lowering regimens based on different drug classes. The investigators pointed out that �although modest independent effects of specific drug classes on stroke or risk of coronary heart disease are not precluded by our findings, the results do suggest that blood pressure lowering is a major component of the benefit conferred by the regimens investigated. Direct evidence is provided by the regimens targeting different blood pressure goals (with various drug classes), which showed larger reductions in stroke and total major cardiovascular events from regimens targeting lower blood pressure goals.�

66. Why do ACEI�s & ARB�s decrease onset of diabetes? Ang II may impair adipocyte proliferation Ang II may promote insulin resistance directly In part, mediated by generation of reactive oxygen species (ROS)

70. Stroke risk reduction associated epidemiologically with a long-term difference of 5-6 mm Hg DBP Combined Morbidity/Mortality in Subgroups The combined morbidity and mortality in the subgroups shows an advantage for valsartan in: Patients <65 and ? 65 years of age Both males and females Patients with EF <27% and ? 27% In the presence or absence of ACE inhibitor therapy Patients not taking ?-blockers as concomitant therapy; while placebo was favored in patients taking ?-blockers In the presence or absence of ischemic heart disease Combined Morbidity/Mortality in Subgroups The combined morbidity and mortality in the subgroups shows an advantage for valsartan in: Patients <65 and ? 65 years of age Both males and females Patients with EF <27% and ? 27% In the presence or absence of ACE inhibitor therapy Patients not taking ?-blockers as concomitant therapy; while placebo was favored in patients taking ?-blockers In the presence or absence of ischemic heart disease

71. CHD risk reduction associated epidemiologically with a long-term difference of 5-6mm Hg DBP Combined Morbidity/Mortality in Subgroups The combined morbidity and mortality in the subgroups shows an advantage for valsartan in: Patients <65 and ? 65 years of age Both males and females Patients with EF <27% and ? 27% In the presence or absence of ACE inhibitor therapy Patients not taking ?-blockers as concomitant therapy; while placebo was favored in patients taking ?-blockers In the presence or absence of ischemic heart disease Combined Morbidity/Mortality in Subgroups The combined morbidity and mortality in the subgroups shows an advantage for valsartan in: Patients <65 and ? 65 years of age Both males and females Patients with EF <27% and ? 27% In the presence or absence of ACE inhibitor therapy Patients not taking ?-blockers as concomitant therapy; while placebo was favored in patients taking ?-blockers In the presence or absence of ischemic heart disease

72. What percent of CHD mortality in hypertensives can be attributed to lipids? Using data from Selby JV. (JAMA 1991; 265:2079) 60 of 185 hypertensives had abnormal lipids Prevalence = 32.4% Relative risk = 14.7 / 4.1 = 3.6 Attributable risk = 45.6% Implies you would only decrease risk for CHD death by 54.4% of expected if you just normalized the blood pressure. This is a conservative estimate of the lipid effect