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