KOLOVOU

Δυσλιπιδαιμίες και υπέρταση

Γενοβέφα Κολοβού

BP and Stroke mortality rate by age

1. Prospective Studies Collaboration. Lancet 2002;360:19032002;360:1903-1913.

ΔΥΣΛΙΠΙΔΑΙΜΙΕΣ ΚΑΙ ΥΠΕΡΤΑΣΗ

In USA, 78% of hypertensive men and 82% of hypertensive women have at least one other CV risk factor

Framingham data,

Kannel, et al 2000

In France 84% of hypertensive men and 77% of hypertensive women have at least one other CV risk factor 2001

Asmar, et al

Οι ασθενείς με υπέρταση συχνά έχουν επιπλέον παράγοντες κινδύνου για ΣΝ

ΔΥΣΛΙΠΙΔΑΙΜΙΕΣ ΚΑΙ ΥΠΕΡΤΑΣΗ ~35% Western Europeans have hypertension and dyslipidemia MONICA study, Tunstall-Pedoe et al 2004

20% UK adults have hypertension and dyslipidemia (9.2 million people) Williams et al 2004 40 % of 51 million USA individuals with ↑BP → TC ≥240 mg/dl 46 % of those with TC ≥240 mg/dl have ↑BP NHANES II study

Table 1. Clinical characteristics of the study population.

Number of patients Age (years) Gender (male/female)

124 62(10) 110/14

Body mass index (kg/m2) 27(3) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Apolipoprotein A (mg/dl) Apolipoprotein B (mg/dl) Smoking (%) Diabetes (%) Hypercholesterolaemia (%) Hypertension (%) Number of arteries stenosed

235(56) 185(143) 39(10) 158(47) 114(24) 96(33) 36 35 80 70 2.2(0.8)

Gensini score

106(113)

Duke Jeopardy score

6.3(4.5)

Kolovou G, et al. CETP gene polymorphisms and severity of coronary stenosis. Clin Invest Med 2006

Table I. Sample characteristics by BMI category and study group CHD Patients

Total Sample

Normoweight (N=98)

Overweight (N=189)

Obese (N=72)

Mean (SD)

Mean (SD)

Mean (SD)

N (%)

N (%)

CHD Pts (N=359) p

N (%)

Mean (SD)

N (%)

Controls (N=248) Mean (SD)

p

N(%)

DM

27 (30)

59 (34)

24 (22)

0.6

110 (34)

0 (0)

↑ BP Smoking

5152% (55) 29 (33)

98 (60) 63 (39)

4461% (72) 32 (53)

0.2 0.0 5

54% 193 (61) 124 (40)

0 (0) 71 (29)

p=0.002 for normoweight vs. overweight; bp=0.001 for normoweight vs. obese; c p<0.001 for normoweight vs. overweight; dp=0.001 for normoweight vs. obese. a

Kolovou et al: Apolipoprotein E, Obesity and Coronary Heart Disease. In Vivo 2008

<0.00 1 0.001 0.008

ΔΥΣΛΙΠΙΔΑΙΜΙΕΣ ΚΑΙ ΥΠΕΡΤΑΣΗ

The risk gradient for blood pressure (systolic and diastolic) is similar to that for serum cholesterol Î the higher the blood pressure, the greater the risk of CHD Persons ↑ TC + ↑ BP → CHD risk is ↑ synergistically

↑ ΑΠ → ↑ κίνδυνος για ΕΜ, ΚΑ, ΑΕΕ και ΝΑ

Σε ασθενείς 40-70 χρονών κάθε ↑ 20 mm Hg της ΣΑΠ ή ↑ 10 mm Hg της ΔΑΠ ↓ ↑ 2× τον κίνδυνο καρδιαγγειακών νοσημάτων

Κατάταξη

Αναμενόμενη αύξηση των θανάτων από στεφανιαία νόσο (ΣΝ) Εκτίμηση 1990

Πρόβλεψη 2020

Αιτία

Αιτία

1

Λοιμώξεις κατώτερου αναπνευστικού

Ισχαιμική καρδιοπάθεια

2

Διαρροϊκές παθήσεις

Μονοπολική μείζων κατάθλιψη

3

Περιγεννετικές καταστάσεις

Τροχαία ατυχήματα

4

Μονοπολική μείζων κατάθλιψη

Αγγειοεγκεφαλική νόσος

5

Ισχαιμική καρδιοπάθεια

COPD*

6

Αγγειοεγκεφαλική νόσος

Λοιμώξεις κατώτερου αναπνευστικού

7

Φυματίωση

Φυματίωση

8

Ιλαρά

Πόλεμος

9

Τροχαία ατυχήματα

Διαρροϊκές παθήσεις

*COPD=Chronic obstructive pulmonary disease

Eur Heart J. J. Supplements.2002;4:F2Supplements.2002;4:F2-F6

Atherogenesis The thrombogenic theory

The inflammatory theory

Κarl von Rokitansky

Rudolph Ludwig Κarl Virchow

1804 – 1878

1821 – 1902

LDL LDL Plt LDL

LDL

LDL ox-LDL

Macrophage

LDL LDL Plt LDL

LDL

LDL ox-LDL

HDL Macrophage

HTN, hemodynamic factor and atheroclerosis

HTN creates areas of low shear stress within arteries, which in turn results in increased endothelial permeability; ↑ duration of lipoprotein contact with the endothelium; ↑ lipoprotein penetration; ↓endothelium-dependent vasodilation.

The Progression from CV Risk Factors to Endothelial Injury and Clinical Events LDL-C

BP

Diabetes

Risk factors

Smoking

Heart failure

Oxidative stress

Endothelial dysfunction

NO

PAI-1

Local mediators

VCAM

Tissue ACE-Ang II

Endothelium

ICAM cytokines Thrombosis

Inflammation

Vasoconstriction

Growth factors matrix

Vascular lesion and remodelling

Proteolysis

Plaque rupture

Clinical endpoints NO Nitric oxide

Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

Inactive peptides

Bradykinin

↑ Vasodilation ↑ Prostacyclin ↑ Nitric oxide ↑ t-PA ↑ Oxidative stress

Protection against the effects of angiotensin II

↑ Vasocostriction ↑ ICAM-1, VCAM-1 ↑ Growth factors ↑ Oxyradical formation ↑ PAI-1 ↑ Smooth muscle cell proliferation ↑ Matrix degradation

↑ Endothelial dysfunction, inflammation, coagulation and atherogenesis

ACE inhibitor

Angiotensin I

Angiotensin II

Atherosclerosis-promoting actions of angiotensin II and protective effects of bradykinin.

Role of Angiotensin II in the Progression of Atherosclerosis

Angiotensin II

Activation of NADH oxidase in endothelial cell Oxidized ↑ O2 generation LDL O2

O2

↑ LOX-1 receptors

↑ LDL ox and uptake by macrophages

↑ Uptake of oxidized LDL

↓ NO

Interference with endotheliumdependent vasodilation

NADH = nicotinamide adenine dinucleotide.

Endothelial cell injury

Accumulation of lipids in plaques

Formation of foam cells

Vaughan DE. Circulation. 2000

Chronic activation of the renin system contributes to end-organ damage

Atherosclerosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction

Stroke

Hypertension

↑Ang II

Ang, angiotensin MI, myocardial infarction

Hypertrophy Fibrosis Remodelling Cell death

Heart failure MI

↓Glomerular filtration rate Proteinuria ↑Aldosterone release Glomerular sclerosis

Renal failure

Death

Adapted from Anderson, Goodfriend, and Phillips In: Hypertension Primer, 2003.

The Progression from CV Risk Factors to Endothelial Injury and Clinical Events LDL-C

BP

Diabetes

Risk factors

Smoking

Heart failure

Oxidative stress

Endothelial dysfunction

NO

PAI-1

Local mediators

VCAM

Tissue ACE-Ang II

Endothelium

ICAM cytokines Thrombosis

Inflammation

Vasoconstriction

Growth factors matrix

Vascular lesion and remodelling

Proteolysis

Plaque rupture

Clinical endpoints NO Nitric oxide

Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

Δραστηριότητα του ecNΟs

Υγιείς

(pmol/min/mg protein)

δραστηριότητα ecNOS

4

3

Ασθενείς με στεφανιαία νόσο

p <0.01#

3.5

2

2.5

1

0

Ομάδα ελέγχου

# p=controls The PERTINENT study, Cokkinos D, Ferrari R et al. Cardiovascular Res 2007;73:237 2007;73:237--46

Δραστηριότητα του ecNΟs επώαση με ορό από: Υγιείς

(pmol/min/mg protein)

δραστηριότητα ecNOS

4

3

p

<0.01#

Ασθενείς με στεφανιαία νόσο Ένταξη

1 χρόνο μετά p < 0.05 ‡

3.5

3.3 2.5

2

2.4

2.9

1

0

Ομ. ελέγχου

# p=controls vs baseline ‡ p= Δ perindopril vs Δ placebo

Placebo Perindopril

Placebo Perindopril

The PERTINENT study, Cokkinos D, Ferrari R et al. Cardiovascular Res 2007;73:237 2007;73:237--46

Αντιαθηρωματική δράση

A:Ομάδα Ελέγχου

B:Ομάδα Διαβήτη + Έλλειψη apoE

C:Ομάδα Διαβήτη+Έλλειψη apoE+περινδοπρίλη apoE+περινδοπρίλη

“Perindopril inhibited diabetes-induced ACE, connective tissue growth factor, and vascular cell adhesion molecule-1 (VCAM-1) over expression in the aorta” Candido R et al. Circulation. 2002;106:2462002;106:246-253

Additionally, the percentages of the patients’ anthropometric characteristics were estimated in a sample of 801 subjects, of which 47% were smokers, 19% had untreated BP, 7% had DM, 40% had CAD and 20% had experienced one MI.

Kolovou G, et al. VHRM, 2005 Kolovou G, et al. AC, 2006 Kolovou G, et al. HJC, 2006

ΔΥΣΛΙΠΙΔΑΙΜΙΕΣ ΚΑΙ ΥΠΕΡΤΑΣΗ

2005 REVISED ATP III CLINICAL SCREENING CRITERIA TO IDENTIFY METS (AHA AND NHLBI) Diagnosis of MetS(any 3 of 5)

Categorical cutpoints

Elevated waist circumference

≥102 cm in men ≥88 cm in women

Elevated TGs

≥150 mg/dl or on drug treatment for elevated triglycerides

Reduced HDL cholesterol

<40 mg/dl in men <50 mg/dl in women Or on drug treatment for reduced HDL-C

Elevated blood pressure

≥130 mmHg systolic blood pressure or ≥85 mmHg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertension

Elevated fasting glucose

≥100 mg/dl or on drug treatment for elevated glucose

ABNORMALITIES ASSOCIATED WITH INSULIN RESISTANCE

Hemodynamic effect × Sympathetic nervous system activity × Renal sodium retention (increased salt sensitivity) × plasma volume expansion Endothelial dysfunction Ø Endothelial-dependent vasodilatation

Healthy vs. CAD and/or insulin resistance pts

265 mg/dl

220 175

140 mg/dl 115 mg/dl

130

Φ.Τ. < 150 mg/dl

1999, Karpe “ Fat intolerance”

Kolovou G, et al. JACN 2003

Normo TG

TGRL

Peripheral cell

Liver

TG TG TG

LDL CE

CETP

HDL CE

CE CE CE

Hyper TG

LDL CE CE

Small dense LDL

TGRL TG TG TG TG TG

CETP

HDL CE CE CE CE CE

Small dense HDL

Food intake with high fat content

Circulation

Suppression of the hepatic release of VLDL by prostprandial insulin secretion

↓cholesterol synthesis

↑cholesterol absorption ↑CM

↓VLDL

↑LDLR

Intestine LPL

Liver

Glycerol TG FFA

CM remnants

VLDL remnants

Lipid oxidation via Krebs cycle or stored in adipose tissue

Kolovou G, Anagnostopoulou K, Daskalopoulou S, Mikhailidis D, Cokkinos D. Clinical relevance of postprandial lipaemia. Curr Med Chem. 2005

Suppression of the hepatic release of VLDL by prostprandial insulin secretion

Food intake with high fat content Insulin resistance

↓cholesterol absortpion ↑CM

↑VLDL ↓LPL

Intestine

Glycerol

Liver

↓TG LDLRRP

↑CM remnants

↑VLDL remnants

Lipid oxidation via Krebs cycle or stored in adipose tissue

TG

↑CETP CE

↑Catabolism of HDL

↓HDL levels

↓LDLR

↓LPL

FFA

↑TG in HDL

↑cholesterol synthesis

TG ↑TG

↑CETP

↑TG in LDL

CE

↑HL

Small dense LDL

↑ FFA ↓

Adipose tissue is an endocrine organ producing adipocytokines (leptin, AGT, TNFα, IL 6, PAI 1, TGF β, adipsin, adiponectin, resistin) and is a prominent source of CETP./1 CETP mediate the transfer of CEs from CE-rich lipoproteins to TG-rich lipoproteins in exchange for TGs. In obese, CETP activity and mass are increased.

Kolovou, et al. PMJ, 2005

ANTIHYPERTENSIVE AGENTS EFFECT ON LIPID LEVELS Diuretics Î Thiazide: higher doses cause modest (often transient) elevations (5–10 mg/dl) of TC, LDL, TGs with little or no effects on HDL Î Loop diuretics: similar to thiazides Î Indapamide: data are inconclusive, but suggest a neutral effect Î Potassium-sparing diuretics: no effect on lipids

ANTIHYPERTENSIVE AGENTS EFFECT ON LIPID LEVELS The effects of antihypertensive drugs on the efficacy of lipid-lowering agents have not been carefully evaluated, but among participants in LRC-CPPT, those who were taking thiazide diuretics did not reduce LDL as much as those who were not using thiazide diuretics Glueck CJ et al Am J Clin Nutr 1986

ANTIHYPERTENSIVE AGENTS EFFECT ON LIPID LEVELS

Calcium channel antagonists and ACE inhibitors Ă&#x17D; have minimal if any effects on serum lipids

ANTIHYPERTENSIVE AGENTS EFFECT ON LIPID LEVELS Alpha-1-adrenergic R blockers (doxazosin, prazosin, terazosin) | Centrally acting alpha-2-adrenergic receptors agonists (a-methyldopa, clonidine) | Central imidazoline receptors agonist (moxonidine) |

Î slight beneficial effect on lipids (↓ TC, LDL)

ANTIHYPERTENSIVE AGENTS EFFECT ON LIPID LEVELS Beta-blockers Without intrinsic sympathomimetic activity (ISA) or alpha-blocking properties Î tend to reduce HDL Î increase TGs Î have variable effects on TC With ISA (celiprolol) and alpha-1-adrenergic blocking properties (nebivolol, labetalol, carvedilol) no changes in lipid levels

ALLHAT BIOCHEMICAL RESULTS Chlorthalidone

Amlodipine

Lisinopril

Baseline

216 (44)

217 (44)

216 (42)

4 Years

197 (42)

196 (41)*

195 (41)*

Baseline

4.3 (0.7)

4.3 (0.7)

4.4 (0.7)*

4 Years

4.1 (0.7)

4.4 (0.7)*

4.5 (0.7)*

TC mg/dL,

Serum potassium – mmol/l,

Estimated GFR† – mL/min/1.73m2 ,mean (SD) Baseline

77.6 (19.7)

78.0 (19.7)

77.7 (19.9)

4 Years

70.0 (19.7)

75.1 (20.7)*

70.7 (20.1)*

mean (SD), * p<.05 compared to chlorthalidone, Ann Intern Med. 1999;130:461-470

ANTIHYPERTENSIVE AGENTS EFFECT ON LIPID LEVELS Some persons will have strong indications for one of these medications (for example, beta-blockers in the post-MI and diuretics in persons with salt-dependent hypertension).

Therefore, they are not contraindicated even in the presence of the dyslipidemia Some persons are not sensitive to the adverse effects of diuretics on lipids, and in others a low-saturated-fat, low-cholesterol diet will blunt or negate these effects.

HYPOLIPIDEMIC AGENTS EFFECT ON BP LEVELS The FDA lists no specific drug interactions between statins and antihypertensive agents; however, patients with some forms of renal disease may be at increased risk for myopathy with statin therapy Fibric acids are more likely to produce myopathy in persons with renal failure; therefore, dosage should be decreased and persons carefully monitored

HYPOLIPIDEMIC AGENTS EFFECT ON BP LEVELS

Bile acid sequestrants may decrease absorption of thiazide diuretics and propranolol, and medications should be given 1 hour before or 4 hours after the bile acid sequestrant No apparent effect with Colesevelam Nicotinic acid may enhance the fall in blood pressure due to antihypertensive vasodilators

HYPOLIPIDEMIC AGENTS EFFECT ON BP LEVELS

HYPOLIPIDEMIC AGENTS EFFECT ON BP LEVELS Possible Mechanisms of the BP Effect of Statins Î improve endothelial function early after administration unrelated to their cholesterol-lowering action Î inhibit the production of reactive oxygen species, contributing to vasodilation Î downregulate the angiotensin II–type 1 receptor

4

1.5 Follow-up (yr) â&#x2C6;&#x2014;Nonfatal MI (including silent MI) and fatal CHD.

3.5

Δυσλιπιδαιμίες και υπέρταση

“In view of the results of the ASCOT trial it seems reasonable to consider statin therapy in hypertensive patients aged less than 80 years who have an estimated 10 years risk of cardiovascular disease 20% or of cardiovascular death (based on the SCORE model) of 5% or more.”

ESC/ESH 2007

ΠΙΘΑΝΕΣ ΕΞΗΓΗΣΕΙΣ ΓΙΑ ΤΙΣ ΠΑΡΑΤΗΡΟΥΜΕΝΕΣ ΔΙΑΦΟΡΕΣ Î Ανεπιθύμητες αλληλεπιδράσεις μεταξύ ατενολόλης ± θειαζίδης και στατίνης Î Ωφέλιμη αλληλεπίδραση μεταξύ αμλοδιπίνης ± περιντοπρίλης και στατίνης

ΔΥΣΛΙΠΙΔΑΙΜΙΕΣ ΚΑΙ ΥΠΕΡΤΑΣΗ Diet and other lifestyle therapies are the essential first steps of therapy for elevations of both blood pressure and cholesterol.

The principles of dietary therapy are similar in both cases and include | reductions of calories, saturated fat, cholesterol, and alcohol consumption | sodium reduction and ample potassium intake are also important for control of hypertension. | The recommended diet should emphasize fruits, vegetables, and lowfat dairy products