Avoiding End Organ DamageDR. SHAHBAZ AHMED KURESHIMBBS, MCPS, D. CARD, D. Med.Sc, FACC, FAHA, FACP, FPAMSConsultant Cardiologist,Head Department of Cardiology and Nuclear Cardiology,Federal Government Services Hospital, Islamabad

Destination

Thus, hypertension management is a public health priority1. WHO, 2002; 2. AHA, 2004Hypertension Represents a Significant Burden on HealthcareWorldwide, hypertension is responsible for62% of strokes149% of heart attacks1

Hypertension is the third leading risk factor for diseaseCauses 7.1 million premature deaths each year14.5% of global burden of disease1

Hypertension represents a high burden on healthcare expenditureIn 2004, the direct and indirect cost of high blood pressure in the US was $55.5 billion; drug costs accounted for $21 billion2

National Health SurveyCirculatory diseases account for over 100,000 deaths a year or 12% of all cause mortality . Overall 18% of adults in Pakistan suffer from HBP, 21.5% in urban areas and 16.2% in rural areas.One in every 3 adults over age 45 suffer from hypertension.Very few Pakistanis with hypertension (

Potentially Preventable Causes of Death

BP and increasing ageKearney et al, Lancet 2005

Prevalence of hypertension is high20002025Prevalence of hypertension (%)Kearney PM et al.,Lancet. 2005;365:217-223.Prevalence of hypertension in people aged 20 years and older

ESH-ESC guidelines, 2003, J HypertensFactors Necessary to Assess the Risk or Target Organ Damage

Risk stratificationTarget organ damageSystolic / diastolic BPLeft ventricular hypertrophyMen > 55; Women > 65 yearsUltrasound: Evidence of thickeningTobacco smokingor plaquesDyslipidemiaIncreased creatininemiaFamily history +Microalbuminuria (malb/creat ratio)Protein C-reactive > 6 mg/dl men: >2.5 mg/mmol women: >3.5 mg/mmol

Hypertension is a leading cause for cardiovascular morbidity9.53.32.45.02.03.52.145.421.312.46.29.97.313.96.322.701020304050NormotensiveHypertensiveCoronary DiseaseStrokePeripheral Arterial DiseaseHeart FailureBiennial Age-Adjusted Rate per 1,00036-Year Follow-up in Patients Aged 35-64 Years1,21. Kannel W.B. et al., JAMA 1996; 275: 1571-15762. Kannel W.B. et al., J Hum Hypertens 2000; 14: 83-90

Vasan et al. N Engl J Med. 2001High-Normal BP and CVD Risk

Lewington S et al. Lancet. 2002; 360:1903-1913.Relationship between (a) systolic blood pressure (SBP) and (b) diastolic blood pressure (DBP) and ischaemic heart disease mortality in one million individuals in the general population. CI, confidence interval. Blood pressure, heart disease and age correlate closely

CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment**Individuals aged 40-70 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressureLewington S, et al. Lancet. 2002; 60:1903-1913. JNC 7. JAMA. 2003;289:2560-2572.CV mortality riskSBP/DBP (mm Hg)012345678115/75135/85155/95175/105

Absolute Risk Of Coronary Artery Disease And Stroke Mortality

Curvilinear Relation Of Blood Pressure And Cardiovascular Risk

Geographical Variation In Hypertension Prevalence In Population Of African And European Ancestry

Age- Dependent Changes In Systolic and Diastolic Blood Pressure In USA

Sympathetic Nervous System

Endothelium-Derived Relaxing And Constricting Factors

Vascular Remodeling Of Small And Large Arteries

The Renin- Angiotensin- Aldosterone System

Schematic Representation Of The Central Role Played By Angiotensin 1 Receptor (AT1R)

Superiority Of Ambulatory Over Office Blood Pressure Measurements

24-Hour Ambulatory Blood Pressure Recording

Relation Between Systolic Blood Pressure And The Rate Of Progression Of Coronary Atheroma

Klausen et al. Hypertension 2005;46:33743210432103020100Cumulative mortality (%)RR of deathRR of CHD10UAE (g/min)10024681012Years from entryUAE 4.8 g/minUAE 4.8 g/minUAE

Arnlov et al. Circulation 2005;112:969751009590Percentage012345678Years< Median MedianSurvival free of CVDAccording to sex-specific median UACRMicroalbuminuria and Incidence of CV events: The Framingham Study

Blood Pressure Risk Stratification (ESH/ESC 2007)Mancia G et al., J Hypertens 2007;25:110587

Blood pressure reductions of as little as 2mmHg reduce the risk of cardiovascular events by up to 10%1

Meta-analysis of 61 prospective, observational studiesOne million adults12.7 million person-years

2 mmHg decrease in mean systolic blood pressure10% reduction in risk of stroke mortality7% reduction in risk of ischemic heart disease mortality1. Lewington S et al. Lancet. 2002;360:19031913.

Fatal and non- fatal eventsMortalityFatal and non- fatal eventsMortality10-40-30-20-100-50Isolated systolic hypertensionStrokeCHDAll CausesCVNon CVStrokeCHDAll CausesCVNon CVSystolicdiastolic hypertension

Relations Between Achieved Blood Pressure Control And Declines In Glomerular Filtration Rate

Idealized Curves Of Cerebral Blood Flow At Varying levels Of Systemic Blood Pressure

Absolute Benefits For The Prevention Of Fatal Nonfatal Cardiovascular Events

Odds Ratio For Cardiovascular Events And Systolic Blood Pressure

Graphical Representation Of Three Hypothetical Relationships Between Levels Of Blood Pressure And Risk Of Cardiovascular Disease

Relationship Between The Net Change In Urinary Sodium Excretion And Systolic Blood Pressure

Mean Cerebral Blood Flow Autoregulation Curves

Trials Comparing The Effect On Primary End Point Of Treatment Based On Different Antihypertensive Drugs

Bakris et al. Am J Kidney Dis. 2000;36:646-661; Bakris et al. Arch Intern Med. 2003;163:1555-1565; Lewis et al. N Engl J Med. 2001;345:851-860.Number of BP MedicationsAntihypertensive Therapy: Number of Agents Required to Achieve BP Goal UKPDS (

An Algorithm For The decision To Manage Patients With Different Average Blood Pressure Levels

Algorithm For Therapy Of Hypertension

Get patients to BP goal Provides 24 hour BP control Has good tolerability Has added protectionWhat qualities do you want to see in an effective Anti Hypertensive agent?

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Marc A. Pfeffer, M.D., Ph.D. (Chair), John J.V. McMurray, M.D. (Co-Chair), Eric J. Velazquez, M.D., Jean-Lucien Rouleau, M.D., Lars Kber, M.D., Aldo P. Maggioni, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., Frans Van de Werf, M.D., Ph.D., Harvey D. White, D.Sc., Jeffrey D. Leimberger, Ph.D., Marc Henis, M.D., Susan Edwards, M.S., Steven Zelenkofske, D.O., Mary Ann Sellers, M.S.N., and Robert M. Califf, M.D., for the VALIANT InvestigatorsVALsartan In Acute myocardial iNfarcTionDr Shahbaz A. KureshiHead, Department of CardiologyFederal Govt. Serv. Hospital, Islamabad

ConclusionIn patients with MI complicated by heart failure, leftventricular dysfunction or both:Valsartan is as effective as a proven dose of captopril in reducing the risk of:DeathCV death or nonfatal MI or heart failure admissionCombining valsartan with a proven dose of captopril produced no further reduction in mortalityand more adverse drug events.Implications:In these patients, valsartan is a clinically effectivealternative to an ACE inhibitor.

Treatment Enables Retardation of the Progression of Renal Disease Early stage Late stage Terminal stageSeverity of renal diseaseIRMA 2MARVALIDNTRENAAL Microalbuminuria Macroalbuminuria ESRD PreventionProtectionBenedictstudy

ConclusionsIn type 2 diabetic pts with microalbuminuria arterial BP was reduced to the same extent in the valsartan and amlodipine groups

AER was significantly reduced in the valsartan group compared with the amlodipine group.

Significantly more pts regressed to normoalbuminuria in the valsartan group

The effect of valsartan on AER was similar in both the normotensive and hypertensive subgroups

First do no harm

Algorithm for Evaluating Patients in whom Renal Artery Stenosis Is Suspected

Path physiology Of Primary Aldosteronism

Mendelian Forms Of Hypertension That Cause Mineralcorticoid- induced Hypertension

The Mechanisms By Which Chronic Diuretic Therapy May Lead TO Various Complications

Theoretical Therapeutic And Toxic Logarithmic And Linear Dose Response Curve

Classification Of Beta- Adrenoreceptor Blockers On The Basic Of Cardioselectivity And Intrinsic Sympathomimetic Activity

USA53.1Canada41.0Mexico21.8Germany33.6Greece49.5England29.2Egypt33.5South Africa*47.6Japan*55.7Taiwan18.0China28.8Worldwide blood pressure control rates in treated hypertensive patients are lowKearney P.M. et al., J Hypertens 2004; 22: 1119; * Data for men onlyTurkey19.8

Simplified Schematic View Of The Adrenergic Nerve

AngiotensinogenAngiotensin IAngiotensin IICEReninChymaseBradykininInactiveK+Na+ACTHOtherAdapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.RAA system targets multiple receptor sitesAldosterone

Kaplan NM & Opie LH. Lancet 2006; 367:168-176.Major mechanisms(1) increased adrenergic drive, as often found in young people (aged 3049 years); (2) high-renin hypertension, as seen in individuals with renal dysfunction;

(3) low-renin hypertension, as recorded in individuals with inherently raised aldosterone concentrations;

(4) increased peripheral vascular resistance (PVR), as seen in elderly patients. CO=cardiac output. =-adrenergic stimulation =-adrenergic stimulation. AII=angiotensin II.Hypertension has a multifactorial origin

Renin

ACE

Non-ACEPathways*AngiotensinogenAngiotensin IIAngiotensin IAT1 receptorARB BlockadeAT2 receptor*not affected by ACE inhibitorsVasoconstrictionHypertrophy and ProliferationOxidation and InflammationPAI-1 expression and release VasodilationNitric Oxide releaseAntiproliferationBlockade of AT1 receptor Activation of AT2 receptorVascular ProtectionAdapted from:Kaschina E and Unger T. Blood Press 2003;12:70-88.Unger T. J Hypertens 1999;17:1775-1786.Angiotensin (AT1) receptor blockade provides vascular protection

Renin profile correlates with CV riskAlderman MH et al. N Engl J Med. 1991;324:1098-1104.

Potentially preventable causes of death*The World Health Organizations (WHO) World Health Report for 2002 states that, worldwide, high blood pressure is estimated to cause 7.1 million deaths, about 13% of the total global fatality and 4.5% of attributable disability adjusted life-years (DALYs).1Across WHO regions, research indicates that about 62% of strokes and 49% of heart attacks are caused by high blood pressure.1In 2004, the American Heart Association (AHA) estimated the direct and indirect cost of high blood pressure in the US to be $55.5 billion.2References Facts and Figures: World Health Report 2002. World Health Organization. Available at http://www.who.int/mediacentre/news/releases/pr84/en (last accessed date 10/2006). AHA. Heart Disease and Stroke Statistics -- 2004 Update. Available at: http://www.americanheart.org/downloadable/heart/1079736729696HDSStats2004UpdateREV3-19-04.pdf (last accessed date 10/2006).

Potentially preventable causes of deathPotentially preventable causes of death*Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

Reference :Kearney PM et al.,Lancet. 2005;365:217-223Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

Reference :1. Kannel W.B. et al., JAMA 1996; 275: 1571-15762. Kannel W.B. et al., J Hum Hypertens 2000; 14: 83-90

Potentially preventable causes of deathPotentially preventable causes of death*9. Vasan RS, Larsen MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345:1291-1297.Studies have shown that risk of CVD is increased even at levels of BP considered to be high-normal. The cardiovascular (CV) event rates of 6589 patients from the Framingham Study who had high-normal, normal, or optimal BP at baseline (as defined above) were recorded over 14 years. Men and women with high-normal BP at baseline had a higher incidence of CVD on follow-up than did those with normal or optimal BP. This relationship was consistent in both men and women, and in middle-aged and elderly subjects. The rate of CV events in persons with normal or optimal BP was low, but a continuous gradient of increasing risk was observed across the 3 BP categories.9 SLIDE *Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

Reference :Lewington S et al. Lancet. 2002; 360:1903-1913Potentially preventable causes of deathPotentially preventable causes of death*CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment

Slide SummaryAccording to a meta-analysis of over 60 prospective studies, the risk of cardiovascular mortality doubles with each rise of 20 mm Hg in systolic blood pressure (BP) and 10 mm Hg in diastolic BP.

Background In a meta-analysis of 61 prospective, observational studies conducted by Lewington et al involving one million adults with no previous vascular disease at baseline, the researchers found that between the ages of 40-69 years, each incremental rise of 20 mm Hg systolic BP and 10 mm Hg diastolic BP was associated with a twofold increase in death rates from ischemic heart disease and other vascular disease. The researchers also noted that when attempting to predict vascular mortality risk from a single BP measurement, the average of systolic and diastolic BP was slightly more informative than either alone, and that pulse pressure was much less informative. The seventh report Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) notes this study result as yet more information linking hypertension to high risk for cardiovascular events.

Lewington S, Clarke R, Qizilbash H, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2003;361:1903-1913.

JNC 7. JAMA. 2003;289:2560-2572.Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

MethodsData from a meta-analysis of 61 prospective, observational studies has provided powerful evidence that throughout middle and old age, blood pressure (BP) is strongly and directly related to vascular mortality.1 These findings show, for example, that a 10 mmHg lower systolic BP is associated over the long-term with a 40% lower risk of stroke death and a 30% lower risk of death from ischemic heart disease (IHD) or other vascular causes. Importantly, within each decade of life between 40 and 89 years the proportional difference in the risk of vascular death associated with a given absolute difference in mean BP is roughly equivalent down to at least 115 mmHg for systolic BP and 75 mmHg for diastolic BP (below which there is little evidence). Thus, there was no evidence of a J curve across all middle and older age groups.Perhaps most striking is the practical implications of these data: even a small, 2 mmHg fall in mean systolic BP would be associated with large absolute reductions in premature deaths and disabling strokes.1 As shown here, a 2 mmHg lower mean systolic BP could lead to a 7% lower risk of IHD death and a 10% lower risk of stroke death.1

Reference :Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:19031913. Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

MethodsMeta-analysis of data from trials of active antihypertensive treatment compared with placebo have shown that blood pressure lowering reduces:1Cardiovascular and total mortalityStrokeCoronary events.

Benefits have been shown in placebo-controlled trials that have used all major antihypertensive drug classes, including:DiureticsBeta blockersCalcium antagonistsAngiotensin-converting enzyme (ACE)-inhibitorsAngiotensin receptor antagonists.

Benefits have been proven:In patients with systolic-diastolic hypertensionIn elderly patients with isolated-systolic hypertension.

Reference :Cifkova R, et al. for the ESH/ESC Hypertension Guidelines Committee. Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertens. 2003;21:10111053

Potentially preventable causes of deathPotentially preventable causes of death*Polypharmacy may be necessary to reach BP goals in hypertension management.45,47,48Trial abbreviations: UKPDS = United Kingdom Prospective Diabetes Study; MDRD = Modification of Diet in Renal Disease; HOT = Hypertension Optimal Treatment; AASK = African American Study of Kidney Disease; RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT = Irbesartan Diabetic Nephropathy Trial.45.Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. 47.Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.48.Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Special report: preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646-661.49. Bakris GL, Weir MR, Shanifar S, et al, for the RENAAL Study Group. Effects of blood pressure level on progression of diabetic nephropathy. Results from the RENAAL study. Arch Intern Med. 2003;163:1555-1565.SLIDE *Potentially preventable causes of deathPotentially preventable causes of death*Potentially preventable causes of deathPotentially preventable causes of death*Potentially preventable causes of death*Potentially preventable causes of deathThe Valsartan in Acute Myocardial Infarction Trial VALIANT.Potentially preventable causes of death*In patients with MI complicated by heart failure, left ventricular dysfunction or both,valsartan is as effective as a proven dose of captopril in reducing the risk of:Death, CV death, or nonfatal MI, or hospital admission for heart failure. Combining valsartan with a proven dose of captopril produced no further reductions in mortality and resulted in more adverse drug events.Implications are that by preserving all the cardiovascular benefits of an ACE inhibitor in this population, valsartan is a clinically effective alternative for high risk patients post-MI.Potentially preventable causes of death*Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

MethodsThe RAAS is stimulated by: Fall in BP Fall in circulating volume Sodium depletionAny of the above stimulate renin release from the juxtaglomerular apparatusRenin converts angiotensinogen to angiotensin IAngiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE)Angiotensin II is a potent Vasoconstrictor Anti-natriuretic peptide Stimulator of aldosterone release from the adrenal glandsAldosterone is also a potent antinatriuretic and antidiuretic peptideAngiotensin II is also a potent hypertrophic agent which stimulates myocyte and smooth muscle hypertrophy in the arterioles

Reference :Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.

Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

MethodsThere is still much uncertainty about the pathophysiology of hypertension. A small number of patients (between 2% and 5%) have an underlying renal or adrenal disease as the cause for their raised blood pressure. In the remainder, however, no clear single identifiable cause is found and their condition is labelled essential hypertension. A number of physiological mechanisms are involved in the maintenance of normal blood pressure, and their derangement may play a part in the development of essential hypertension. It is probable that a great many interrelated factors contribute to the raised blood pressure in hypertensive patients, and their relative roles may differ between individuals. Among the factors that have been intensively studied are salt intake, obesity and insulin resistance, the reninangiotensin system, and the sympathetic nervous system. In the past few years, other factors have been evaluated, including genetics, endothelial dysfunction (as manifested by changes in endothelin and nitric oxide), low birth weight and intrauterine nutrition, and neurovascular anomalies.

Reference:Kaplan NM & Opie LH. Lancet 2006; 367:168-176Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

Reference :Kaschina E and Unger T. Blood Press 2003;12:70-88.Unger T. J Hypertens 1999;17:1775-1786Potentially preventable causes of deathPotentially preventable causes of death*GLB.IRB.07.11.03071022b-Irbe

MethodsThe prognostic value of plasma-renin activity was tested in a systematic work-site treatment program in 1717 subjects with mild to moderate hypertension (mean age 53 years).

The incidence of myocardial infarction during 8.3 years of follow-up was 14.7 events per 1000 person-years among subjects with a high renin profile, 5.6 among those with a normal renin profile, and 2.8 among those with a low renin profile.

The renin profile before treatment remained independently associated with the subsequent risk of myocardial infarction, but not with stroke or noncardiovascular events (after adjustment for race, age at entry, sex, serum cholesterol levels, smoking status, electrocardiographic evidence of left ventricular hypertrophy, blood glucose level, body-mass index, history of cardiovascular disease or treatment, blood pressure, and use of beta-blockers).

Reference: Alderman MH et al. N Engl J Med. 1991;324:1098-1104.Potentially preventable causes of death