Role of the Renin–Angiotensin–Aldosterone System Inhibition Beyond BP Reduction

Hypertension Mediated Organ Damage : How We Prevent It?The Role Of RAAS In Cardiovascular Continuum.Changes in Arterial Diameter in Patients with Arteriosclerosis or Atherosclerosis.Not All Angiotensin-Converting Enzyme Inhibitors Are Equal.Question : ACEIs vs. ARBs�Is One Class Better For Cardiovascular Diseases?BP Variability .Central BP
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Vascular Age &
Arterial Stiffness.Achieving BP Goals.

1. Role of the Renin–Angiotensin–Aldosterone System Inhibition Beyond BP Reduction   Magdy El- Masry Prof. of Cardiology Tanta University Hypertension Mediated Organ Damage : How We Prevent It?

2. Risk Doubled Risk Halved   20 / 10 Rule

3. Lower your number Lower your risk Benefits of Lowering Blood Pressure

4. Benefits Beyond BP Lowering ? : ACEIs vs. ARBs Treat the patient, not the number? More Than Just Numbers   If you could treat the patient, not just the numbers That would be great

5. RAAS inhibitors : Evolution of benefits Heart / Blood Vessels /Brain / Kidney → HMOD Beneficial effects of BP lowering therapy in hypertension : (HMOD regression and cardiovascular risk reduction with antihypertensive treatment)

6. Historical Perspective The history of the discovery of the renin-angiotensin system began in 1898 with the studies made by Tigerstedt and Bergman, who reported the pressor effect of renal extracts ; they named the renal substance renin based on its origin.  The RAAS has been discovered for more than a century

7. Physiological and detrimental roles of RAAS molecules in cardiac, vascular tissues and kidneys . Aldosterone and Ang II are the principal RAAS molecules involved in cardiovascular and renal system changes during hypertension. Both molecules are also involved in the physiological control of blood pressure (blue text), directly impacting cardiomyocytes , kidney epithelial cells, and vascular smooth muscle cells. During hypertension, excesses of these molecules have also been linked with cardiovascular and kidney tissue hypertrophy and fibrosis (red text)

8. The term ‘cardiovascular continuum’ was first coined by Dzau and Braunwald in 1991 to describe a new paradigm for cardiovascular diseases

9. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:1244–1263.

10. The cardiovascular (CV) [upper curve] and renovascular (lower curve) disease continuum. CV risk factors such as arterial hypertension, dyslipidaemia , diabetes mellitus and smoking facilitate the generation of atherosclerotic lesions, leading to coronary artery disease, symptomatic ischaemia and, via plaque rupture and acute coronary thrombosis, to acute coronary syndromes and myocardial infarction (MI). Persistent cardiac structural damage reduces contractility and is the basis of left ventricular dilatation and remodelling , which leads to chronic congestive heart failure and, ultimately, premature death. Renal endothelial dysfunction may be followed by microalbuminuria , macroproteinuria , nephrotic syndrome and, finally, end-stage renal disease  The Role Of RAAS In Cardiovascular Continuum

11. Changes in Arterial Diameter in Patients with Arteriosclerosis or Atherosclerosis. Individuals with arteriosclerosis are affected by changes in the thickness of the blood vessel wall owing to smooth muscle proliferation, which alters the size of the lumen and stiffness of the artery, and leads to impaired blood circulation. Atherosclerosis is characterized by arterial stenosis, with presence of plaques that restrict blood flow through the lumen.

12. LVH indicates left ventricular hypertrophy; IMT, intima-media thickness; PP, pulse pressure; BP, blood pressure. Cycle of microvascular damage in hypertension. Is Microcirculation a Culprit or Victim of Hypertension? Indeed, there may be a cyclical process of damage and hypertension that is self-perpetuating; however, the majority of available evidence points to the microcirculation being altered in response to sustained elevation in pressure after the onset of essential hypertension MAP = 1/3 (SBP – DBP) + DBP

13. RAAS Blockade Currently 4 families of RAAS inhibitors are approved by FDA

14. *1 in combination with a potassium-sparing diuretic, as indicated *2 symptomatic treatment for angina pectoris Recommendations for drug treatment of arterial hypertension with additional indications for first-line treatment because of further underlying diseases.

15. Medications aimed at inhibiting the RAAS have been used extensively for preventing cardiovascular and renal outcomes in patients with diabetes .

16. ACEIs & ARBs monitoring requirements Care should be taken in patients on diuretic therapy (monitor for hypotension )

17. Not All ACEIs Are Equal

18. Perindopril, in the EUROPA study, and ramipril , in HOPE trial , are the only ACE inhibitors that have data showing their therapeutic association with the prevention of CV events and lower CV mortality rates in patients with or at high risk for CAD , who have normal LV function Not All Angiotensin-Converting Enzyme Inhibitors Are Equal Ramipril Perindopril

19. “Ever since the HOPE study, published in 2000, ACEIs have become a sacred cow and nobody dared to say anything against them” The Heart Outcomes Prevention Evaluation (HOPE)  study The trial confirmed beyond a doubt the cardiac and renal protective benefit of ACE inhibition and extended the patient base in whom ACE inhibition has been proven effective.

20. Question : ACEIs vs. ARBs Is One Class Better For Cardiovascular Diseases? Benefits Beyond BP Lowering ? Breaking a Scientific Taboo

21. ACEIs = ARBs ARBs < ACEIs

22. The Problem With ACE Inhibitors Between 5% and 20% of patients treated with ACE inhibitors experience a dry persistent cough that requires termination of therapy “ACE cough” results from the concurrent blockade of bradykinin breakdown

23. The effects of angiotensin II inhibition and improvement in bradykinin availability ↓Angiotensin II ↑ Bradykinin ↓Vasoconstriction ↑Vasodilatation ↓Adhesion of monocytes ↑ Antiadhesion of monocytes ↓SMC growth , proliferation , and migration ↑Increased eNOS expression ↓Increased PAI-1 and thrombogenesis ↑Increased t-PA and fibinolysis ↓Matrix degradation ↑ Antiremodeling effect ↓Oxygen free radical production ↑Antioxidant effect ↓Endothelial dysfunction ↑Preserved endothelial function The decrease in angiotensin II levels prevents a number of deleterious cardiovascular effects, while the increase in bradykinin has cardioprotective consequences ACE Inhibition : Vasculo - protection

24. Most guidelines for the management of patients with  cardiovascular  disease recommend  angiotensin-converting enzyme (ACE) inhibitors  as first-choice therapy, whereas  angiotensin receptor  blockers (ARBs) are merely considered an alternative for ACE inhibitor–intolerant patients.

25. OFFICE BLOOD PRESSURE

26. Revolutionizing Hypertensive Care : Beyond The Office Horizon Certain factors independently increase CV risk , beyond clinical BP Central BP BP Variability Vascular Age & Arterial Stiffness

27. Central BP Why is central BP important?

28. Central Blood Pressure The term 'central blood pressure' usually refers to the pressure in the aorta near the heart.

29. Brachial BP Central BP

30. Changes in contour and magnitude as the BP wave moves distally. Central Peripheral

31. Central Blood Pressure Measurement Any Added Value?

32. Persistent Systolic Hypertension ( brachial ) on a Single Agent Clinical Question: Increase Dose or Add Other Medication ?. The central pressure readings provided support for not altering current management . Guiding Hypertension Management Using Central Blood Pressure

33. Central aortic pressure Some studies and meta-analyses have shown that in hypertensive patients , central BP predicts CV events and that there is a differential effect of antihypertensive drugs on central compared with brachial BP.

34. Comparative effect of anti-hypertensive drugs and nitrates on central systolic pressure European Heart Journal , Volume 35, Issue 26, 7 July 2014, Pages 1719–1725

35. Vascular Age & Arterial Stiffness Why is vascular age important? A person whose vascular age is older than his or her chronological age may be at increased risk of developing cardiovascular disease later in life.

36. You're as old as your arteries , which doesn't always equal the number of candles on your birthday cake. How old are your arteries? Two currently available tools estimate artery "age" using pulse wave velocity and carotid intima-media thickness . 

37. The effects of early vascular aging may best be managed by early intervention . The graph above shows early vascular ageing along the red arrow, compared to normal vascular ageing along the blue arrow. Early vascular ageing may lead to premature cardiovascular complications. Early intervention can help to delay these events.

38. Components of healthy vascular aging. Higher blood pressure and stiffening of the large elastic arteries are associated with unhealthy vascular aging . With a shifting profile toward healthy vascular aging, blood pressure is lowered to a nonhypertensive range, and arterial stiffness is also reduced.

39. Systole Aortic Stiffening and Early Wave Reflection Diastole Systole Young compliant arteries : Normal PW velocity (8 m/sec) Elderly stiff arteries : Increased PW velocity (12 m/sec) (1) Ventricular-Vascular coupling (2)  coronary blood flow (1) Ventricular-vascular mismatch (2) The reflected wave increases or “augments” central SBP during late systole:

40. For the determination of aortic PWV it is necessary to define when the arterial blood is injected into the aorta what is the starting point of the arterial pulse wave. It corresponds with the opening of the aortic valve what is characterised by the B-point in the ICG wave form. To detect the arrival of the pulse wave in the femoral artery a cuff is placed on the upper leg which has a constant pressure of about 80 mmHg close to the diastolic blood pressure. This cuff allows to measure a pressure pulse wave in which the slope rise onset is defined (F-point). The time delay between the B-point in the ICG (opening of the aortic valve) and the F-point in the pressure pulse wave defines the propagation time (PT) of the arterial pulse wave in the aorta. For the calculation of the aortic pulse wave velocity it is necessary to measure the distance (d) between the middle of the thigh cuff and the Jugulum to approximate the length of the aorta. Pulse Wave Velocity Measurement principle

41. All antihypertensive drugs , by reducing BP, reduce arterial stiffness, as the reduction in BP unloads the stiff components of the arterial wall, leading to a passive decrease in PWV. Pharmacodynamic RCTs and meta-analyses suggest that ACE inhibitors and ARBs may reduce PWV beyond the effect of BP lowering on a long-term basis. Arteriosclerosis and increased arterial stiffness The aortic pulse wave velocity (PWV) is the most widely validated and universally accepted measure of arterial stiffness . It is known that aortic PWV increases with age and blood pressure. The higher the PWV the higher the arterial stiffness.

42. Blood Pressure Variability yo-yo BP

43. Different types of BPV, their determinants, and prognostic relevance for CV and renal outcomes. AHT, antihypertensive treatment; eGFR , estimated glomerular filtration rate; ESRD, end-stage renal disease; MA, microalbuminuria ; MI, myocardial infarction; SOD, subclinical organ damage. *Assessed in laboratory conditions. †Cardiac, vascular, and renal SOD. ‡BPV on a beat-by-beat basis has not been routinely measured in population studies.

44. Is the ‘Rule of Halves’ in Hypertension Still Valid?

45. Achieving BP Goals Medications Adherence Combination Therapy Optimizing hypertension treatment

46. ESC/ESH vs. ACC/AHA guideline 

47. USA ACC/AHA 2017 Europe ESH/ESC 2018

48. Achievement Of BP Goals : Six Steps

49. Drugs for  Hypertension The A,B,C,D drug classes Treatment of HTN : First‐line drugs In the absence of any compelling condition, any of the following three classes of agents can be used as a first‐line therapy : Thiazide diuretic ACE‐I or ARB CCB

50. Core drug treatment strategy for uncomplicated hypertension The core algorithm is also appropriate for most patients with HMOD , cerebrovascular disease, diabetes, or PAD.

51. Drug Combinations

52. Patients suitable to receive a two-drug combination with either RAS blocker/calcium channel blocker (CCB) or RAS blocker/thiazide diuretic. D C A Dual Antihypertensive Therapy

53. + hydrochlorothiazide Diuretic RAAS Blocker CCB

54. C C A

55. Advantages of fixed-dose combinations versus monotherapy and separate agents A promising choice in hypertension treatment : Fixed-dose combinations