调脂治疗的新方法
Frequency Distribution of Serum Homocysteine in Healthy Men and Women
Frequency %
Serum Homocysteine Concentration (?mol/L)
Factors Influencing Serum Homocysteine Levels
Genetic
Cystathionine Synthase Deficiency
5,10 - METHF
1o Deficiency
Partial Deficiency - Thermolabile
Nutritional Deficiencies
Folate
B6
B12
Other Factors
Renal Failure
Hypothyroidism
Drugs
Dilantin
Methotrexate
Niacin
Plasma Homocysteine and Mortality in CHD Patients
Prospective Evaluation of 587 CHD Patients, Followed for 4.6 Years
Fasting Plasma Homocysteine Measured at Baseline
Strong, Graded Relationship between Homocysteine Levels and All-Cause Mortality
Nygard et al. N Eng J Med. 1997;337:230-236.
Homocysteine Level (?mol/L)
Mortality Ratio
9 - 14.9
15 - 19.9
?20
1.9
2.8
4.5
Relation between Plasma Homocysteine Level and Mortality
Nygard et al. N Eng J Med. 1997;337:230-236.
Prospective Case-Cohort Study of CHD Incidence and Homocysteine: ARIC Results
3.3 year follow-up in ARIC population (15,792 subjects), with 232 incident CHD cases compared to 537 reference subjects
tHcy was not associated with CHD incidence after controlling for all CHD risk factors. Folate, B12 and B6 levels also not predictive
No genetic determinants (MTHFR, CBS) were associated with CHD
Conclusion: tHcy is not an independent risk factor for CHD
Circulation 1998;98:204
Homocysteine, Vitamins and Cardiovascular Disease
Authors suggest that tHcy and CVD relationship can be explained through several possibilities
tHcy is elevated because of the presence of vascular disease
Low levels of folate, B6 and B12 could be the primary cause of CHD, and tHcy is a marker.
tHcy is directly causal to atherosclerosis development
tHcy may increase CHD risk other than atherosclerosis— thrombosis, inflammation
Circulation 1998;98:196
Homocysteine, Diet and Cardiovascular Disease: AHA Science Advisory Report
Most, but not all, prospective studies suggest an increased risk of CAD, stroke and peripheral vascular disease with homocysteine levels >15 ?mol/L.
May be a graded relationship between homocysteine levels >10 ?mol/L and subsequent total and CHD death.
No clinical trials have been done to evaluate effect of lowering homocysteine.
Do not recommend routine homocysteine screening except in high-risk individuals or cases of premature CHD.
Recommended treatment is folate 1 mg, pyridoxine (B6) 25–50 mg and B12 0.5 mg daily.
Circulation 1999;99:178-182
Planned Randomized Clinical Trials of Homocysteine Lowering
VISP (Vitamin Intervention for Stroke Prevention)—US
N = 3600 with history of stroke or TIA
Treatment—Folate 2.5 mg/B6 25 mg vs. folate 0.2 mg/B6 1 mg
SEARCH (Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine)—UK
N = 12,000 with/without vascular disease
Treatment—Folate 2 mg/B12 1 mg vs. placebo with/without simvastatin 20 or 80 mg/day
Planned Randomized Clinical Trials of Homocysteine Lowering
WACS (Women’s Antioxidant and Cardiovascular Disease Study)—US
N = 8000 women with/without vascular disease
Treatment—Folate 2.5 mg/B6 50 mg/B12 1 mg vs. placebo
CHAOS–2 —UK
N = 4000 with CHD
Treatment—Folate 5 mg vs. placebo
Intracellular Oxidative Defense
Superoxide dismutase neutralizes superoxide anions. It contains zinc and copper.
Glutathione peroxidase catabolizes H2O2. It contains selenium.
Catalase removes H2O2 from the cell and it contains iron.
Extracellular Oxidative Defense
Vitamin E (alphatocopherol) and beta carotene are carried in LDL and HDL, and are natural antioxidants
They protect PUFA oxidation in LDL and cell membranes
Tocopherol radicals, formed in quenching superoxide anions, are regenerated to alphatocopherol by vitamin C
Clinical Trials With Antioxidants
Clinical Trials With Antioxidants
Linxian Cancer Prevention Trial
29,000 males and females
Beta carotene 15 mg + alphatocopherol 30 mg + selenium
Follow-up for 5 years
Reduced cancer mortality but no effect on CHD
Nutriceuticals and Cardiovascular Health
Nutriceuticals and Cardiovascular Health
Indicated Patient Population
The LIPOSORBER? LA-15 System is indicated for the following high risk patient population for whom diet and maximum tolerated combination drug therapy has either been ineffective or not tolerated:
Patients with LDL-C ?200 mg/dL with documented CHD
– OR –
Patients with LDL-C ?300 mg/dL
The Lipsorber? LA-15 System
Advantages of Liposorber? LA-15 System
High selectivity for Apo B containing lipoproteins (LDL, VLDL, Lp(a))
Little or no effect on other plasma components such as HDL, albumin or IgG
Automated regenerating system
Disposable system
Theory of LDL-C Lowering by the Liposorber? LA-15 System
Baseline Level on Intensive Diet and Maximum Tolerated Drug Therapy
(Still at High Risk)
LIPOSORBER? Treatment
Level on Diet Therapy
Drug Therapy
Diet Therapy
LDL-C Level
Time
Pre-treatment Level
Time Average Level
Post-treatment Level
Summary of Safety
Low incidence of venous access problems. Only 2.4% of treatments were not completed and only 7.8% of patients discontinued due to venous access problems
Low incidence of adverse events after 4,936 treatments. Hypotension most common adverse reaction with an incidence of 0.8% in 33.8% of patients
After analysis of over 30,000 laboratory evaluations, no clinically significant changes related to LIPOSORBER? therapy
Acute Percentage Reductions
Summary of Effectiveness
Selective removal of Apo B containing lipoproteins (Acute LDL-C lowering of 73-83%)
Time average LDL lowering 42-56%
Retrospective analysis of cardiovascular events showed at 44% reduction of event rates on LIPOSORBER? therapy
Long-term Effects of LDL-Apheresis on Cardiac Events
Patients:
64 Patients with Familial Hypercholesterolemia
10 Homozygotes, 54 Heterozygotes
Treatment:
LDL-Apheresis and Medication
Follow-Up:
2.5 Year Observation of Coronary Events Including:
Cardiac Death, Coronary Revascularization, Coronary Angioplasty, Atherectomy, CABG, MI or Cerebrovascular Event
Results:
44% Reduction in Event Rate During 2.5 Year Observation Period When Compared to 5 Year Medication Only Period Prior to LDL-Apheresis Treatment
Gordon et al. Am J Cardiol 1998; 81:407-411
Long-term Efficacy of LDL-Apheresis on Coronary Heart Disease in FH
Patients:
Heterozygous FH with CHD
Treatment:
LDL-Apheresis and Medication: (N=43)
Medication Only: (N=87)
Follow-Up:
6 Years Observation of Coronary Events Including Non-Fatal MI, PTCA, CABG and CHD Death
Mabuchi et al. Circulation. 1998; 82:1489-1495.
Kaplan-Meier Curves Showing the Proportion of Patients Without Any Coronary Events:
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1
0
2
3
4
5
6
7
8
9
10
11
Medication
p = 0.0088
LDL-Apheresis
Years
Proportion of Patients
Without Any Event
Mabuchi et al. Circulation 1998; 82:1489-1495
Reprinted