Familial Hypercholesterolemia and Statin Drugs
by Jeffrey Dach MD
Left image: Red arrows: Heavily calcified coronary artery on CAT Scan.
A Major Dogma of Mainstream Medicine
One
of the major dogmas of mainstream medicine is the miraculous benefit
of statin drugs in the battle against atherosclerotic heart disease. I
have written a number of previous articles which review the medical
studies on this showing that statin drugs actually do have justifiable
use in certain segments of the population, namely middle aged men with
known heart disease. However, statin drugs are not justified in
women, the elderly or in the
primary prevention setting. This is true because in
women,
the elderly and in the
primary prevention there is no mortality benefit to outweigh the adverse effects.
Familial Hypercholesterolemia- Higher Risk of Heart Disease
How
about the sub-group of the population with a genetic mutation called
familial hypercholesterolemia, in which the serum cholesterol is
markedly elevated because of a mutation in the LDL receptor? This is a
common mutation affecting one in five hundred people.(1)
Left Image: Normal Coronary Artery with No Calcification (Red Arrows) CAT Scan.
Mainstream
medicine says that this genetic trait, familial elevated cholesterol
(usually above 300), carries a higher risk for atherosclerotic heart
disease, and increased mortality at a young age. In the heterozygous
condition, the risk of a “coronary event” by the age of 60 years
without treatment is about 50% in men and 30% in women.(1) Surely, if
statins drugs have any utility, it must be for this group of people
with elevated cholesterol due to a genetic disease.
Case Report- A Woman With Multiple Thyroid Nodules on Statin Drugs
Ann,
a 61 year old real estate agent and grandmother came to see me in the
office because of a number of tiny thyroid nodules which had been
previously biopsied showing an indeterminate result. They couldn’t
decide if it was benign or malignant, so her doctors recommended thyroid
surgery with total thyroidectomy, “just to be sure”.
Thinking
this a bit hasty, Anne came to see me for a second opinion. I
explained to Anne multiple tiny thyroid nodules were quite common in
the population, most likely of no clinical significance.
My previous article,
The Thyroid Nodule Epidemic , discussed this.
I suggested we follow the nodules with serial ultrasound studies while providing medical treatment to shrink the nodules.
Statin Drug for High Cholesterol
In
addition, Anne had been taking a statin drug for high cholesterol and
had obvious adverse drug effects of muscle weakness, muscle pain and
memory loss.
Anne’s lab panel showed a cholesterol of 240 which I
consider faily normal for women. My usual approach in this scenario
is to suggest a Coronary Calcium Scan to assess the amount of
underlying arterial plaque and to answer the question, “Does Anne need
statin drugs”?
Anne’s calcium score test result came back “Zero”,
meaning her arteries are clean with no significant blockage, and
there is no need for a statin drug to prevent heart disease, as there
was nothing there to prevent.
One Year Later
One
year later, Anne was relieved and happy to learn the follow-up
ultrasound scan showed the thyroid nodules were smaller in size,
indicating that Anne certainly did not need thyroid surgery.
Also
at this same one year follow up visit, a repeat cholesterol lab panel
showed that Anne’s cholesterol, off the statin drug, had gone up to
330. The cholesterol had previously been 241 while taking a statin
drug.
Above left image: chemical structure of cholesterol courtesy of wikimedia commons
It Has Always Been Elevated
I
then asked Anne if her cholesterol had ever been elevated in the past,
and she said yes, it has always been elevated in the 300′s her whole
life. Not only that, her parents both have high cholesterol (in the
300′s), and her sisters and brother also have the same thing. After
hearing this, in one of these “Aha moments”, I said to Anne, “
you must have familial hypercholesterolemia !”
Statin Drugs for Familial Hypercholesterolemia (FHC)
This
complicates the issue. Indeed, Anne’s mainstream medical doctor has
been giving Anne a statin drug for the past 10 years to lower her
cholesterol from 330 to 240. In spite of the “Zero” calcium score,
should Anne be taking a statin drug because of the familial
hypercholesterolemia (FHC), a risk factor for heart disease ?
Simon Broome Familial Hyperlipidaemia Registry in the UK
The answer comes from a 2008 study from the Simon Broome Familial Hyperlipidaemia Registry in the United Kingdom.(1,2)
Left Image: Satellite Photo of the UK, United Kingdom courtesy of wikimedia commons.
In
this study, Three Thousand Four hundred (3400) patients with familial
hypercholesterolemia (FHC) were recruited from 21 clinics in the UK and
followed for 26 years (46,580 person-years).(1) What did they find?
Here is a quote from the study:
“Familial
hypercholesterolaemia is associated with a substantial excess
mortality from coronary heart disease in young adults but may not be
associated with a substantial excess mortality in older patients. “(2)
Mortality Depends on Age
The authors looked at data both before and after the availability of statin drugs.
“Before
statin drugs were available, mortality from coronary disease was
increased nearly 100-fold in young adults with FHC aged 20–39 years,
and increased about 4-fold for patients aged 40–59 years, but in those surviving through middle age, risk was similar to the general population.” (1)
In
other words, if a patient survives past 60 with no heart disease, then
they are no longer at increased risk. They have the same risk as the
general population.
They went on to say:
“Both before and after statins became widely available, there was no excess coronary mortality in patients aged >60 years without known coronary disease. Patients surviving into older age before statins became available were therefore likely to be a highly selected group at lower risk of coronary disease.”(1)
A Highly Selected Group at Lower Risk of Coronary Disease
The
Simon Broome Registry of FHC answers our question.(1,2) At age 61,
Anne still has no history of heart disease, and indeed her calcium
score of zero indicated no plaque and no heart disease. Therefore, Anne
must be a member of a “highly selected group at lower risk of coronary
disease”.
If Anne’s high cholesterol over a lifetime placed her
at risk, surely she would have developed some evidence of heart
disease by now. The fact that her calcium score is low means that Anne
is at low risk for heart disease. For Anne, adding a statin drug to
prevent heart disease is not necessary and ill advised, since Anne is
not at risk. Statin drugs carry significant adverse effects with
reduced memory and cognitive function, muscle pain, neuropathy etc.
Reduce Cholesterol Naturally
The
Simon Broome Registry study was re-assuring. Anne felt comfortable
avoiding the statin drugs, and instead use Bergamot, a citrus food
supplement called
CholestePurePlus.(3,4)
Studies show a 25-30% reduction in cholesterol with Bergamot without
adverse side effects associated with statin drugs.(4)
In
addition, we plan to follow Anne’s calcium score with an annual
Coronary Calcium Score. Should Anne’s calcium score increase,
indicating more plaque formation, then a more aggressive form of
intervention would be justified.
Articles with Related Interest
Heart Disease Vitamin C and Linus Pauling
Getting Off Statin Drug Stories
How to Reverse Heart Disease with the Coronary Calcium Score
Cholesterol Lowering Drugs for the Elderly, Bad Idea
Cholesterol Lowering Statin Drugs for Women Just Say No
Jeffrey Dach MD
Links and References
Simon Broome Familial Hyperlipidaemia Register Group 2008
Eur Heart J. 2008 Nov;29(21):2625-33.
Reductions in all-cause, cancer, and coronary mortality in
statin-treated patients with heterozygous familial
hypercholesterolaemia: a prospective registry study.
Neil A, Cooper
J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries
SE.Source NIHR School of Primary Care Research, Division Public Health
and Primary Health Care, University of Oxford, Old Road Headington,
Oxford, UK.
Aims To examine the changes in coronary,
all-cause, and cancer mortality in patients with heterozygous familial
hypercholesterolaemia (FH) before and after lipid-lowering therapy with
statins.
Methods and results A total of 3382 patients
(1650 men) aged <80 years were recruited from 21 lipid clinics in
the United Kingdom and followed prospectively between 1980 and 2006 for
46 580 person-years. There were 370 deaths, including 190 from
coronary heart disease (CHD) and 90 from cancer. The standardized
mortality ratio (compared with the population in England and Wales) was
calculated before and from 1 January 1992. In patients aged 20–79
years, CHD mortality fell significantly by 37% (95% CI = 7–56) from
3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction
in CHD mortality from 2.0-fold excess to none, with a smaller
reduction of nearly 25% in patients with established disease. Coronary
mortality was reduced more in women than in men. In patients without
known CHD at registration, all-cause mortality from 1992 was 33%
(21–43), lower than in the general population, mainly due to a 37%
(21–50) lower risk of fatal cancer.Introduction
Familial
hypercholesterolaemia (FH) is an autosomal co-dominant disorder.1
Defects in at least three different genes that code for proteins
involved in hepatic clearance of low-density lipoprotein-cholesterol
(LDL-C) can cause FH. These include, most commonly, mutations in the
gene coding for the LDL-receptor that removes LDL,2 much less commonly
in the gene for Apolipoprotein B which is the major protein of the LDL
particle, and rarely in the gene coding for an enzyme called PCSK9
involved in degrading the LDL receptor.3 In all cases, this results in
an accumulation of LDL in the plasma from birth, and to subsequent
development of tendon xanthomas, xanthelasmas, and atheroma.1
In
the heterozygous condition, the cumulative risk of a coronary event by
the age of 60 years without effective treatment is at least 50% in men
and ∼30% in women. Coronary disease occurs ∼10 years earlier in men than in women, with a marked increase in women post-menopausally.4–6
Before
effective treatment with HMG-Co reductase inhibitors (statins) became
available, mortality from coronary disease was increased nearly
100-fold in young adults aged 20–39 years, and ∼4-fold for patients
aged 40–59 years, but in those surviving through middle age risk was
similar to the high rates of CHD in the general population of England
and Wales.7,8
In most European populations, heterozygous FH affects about one in 500 individuals,
but no randomized placebo-controlled clinical outcome trials of statin
treatment have been conducted for ethical reasons. Clinical management
is therefore largely based on extrapolation from the results of
cholesterol-lowering trials conducted in patients with polygenic
hypercholesterolaemia;8 from evidence using carotid intima-medial
thickness as a surrogate outcome;9 and from a small number of
prospective observational studies. The latter include the Simon Broome Register of Familial Hyperlipidaemia, which is a register of patients with heterozygous FH recruited from 21 lipid clinics in Great Britain.7
Earlier results from the register suggested that the prognosis for the
heterozygous condition had improved since the introduction and
widespread use of statins.10
The aim of this paper was to extend our previous reports7,10–13 by studying an enlarged cohort of 3382 heterozygous patients followed for up to 26 years until the end of 2006,
by when the exposure had more than doubled to 46 580 person-years.
This has allowed us to examine more informatively the changes in
mortality compared with the general population both before and after
the routine use of statins.Principal findings : This large long-term
prospective registry study of 3382 patients with heterozygous familial
hypercholesterolaemia demonstrates a statistically significant reduction in coronary mortality of about one-third since the widespread use of statins.
Primary prevention resulted in a halving in risk of fatal coronary events,
with a smaller reduction of nearly one-quarters in patients with
established disease. Mortality was reduced more in women than in men for
both primary and secondary prevention. Importantly, in patients
without known coronary disease at registration, all-cause mortality was
significantly lower than in the general population, mainly due to a
reduction of more than one-thirds in the risk of fatal cancer. The data
also confirm our earlier findings that FH patients are not at a higher
risk of fatal stroke.11
However,
the Cholesterol Treatment Trialists’ Collaborators systematic
prospective meta-analysis,8 which reported the efficacy of
cholesterol-lowering treatment using individual patient data for 90 056
participants in 14 randomized trials of statins, found a similar
proportional reduction in major coronary events irrespective of age,
sex, or previous coronary disease. This differs from the pattern of
mortality evident in different sub-groups in our study.
Coronary mortality: We found that, before and after statins became widely available, there was no excess coronary mortality in patients aged >60 years without known coronary disease at registration
Patients
surviving into older age before statins became available were
therefore likely to be a highly selected group at lower risk of
coronary disease.
All-cause and
cancer mortalities: All-cause mortality was significantly reduced by
about one-third in patients without known coronary disease at
registration, which was mainly due to a reduction in cancer
mortality.This is probably attributable to close adherence to advice
given as part of routine clinical care to be physically active, make
dietary changes,30 avoid obesity,31 and stop smoking.
No increased mortality for men or women after age 60 in familial hypercholesterolemia.
2)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1671226/?page=1 BMJ. 1991 October 12; 303(6807): 893–896.
Risk
of fatal coronary heart disease in familial hypercholesterolaemia.
Scientific Steering Committee on behalf of the Simon Broome Register
Group.
OBJECTIVES–(a) To determine the excess mortality from
all causes and from coronary heart disease in patients with familial
hypercholesterolaemia; (b) to examine how useful various criteria for
selective measurement of cholesterol concentration in cardiovascular
screening programmes are in identifying these patients.
DESIGN–Prospective cohort study. SETTING–Eleven hospital outpatient
lipid clinics in the United Kingdom. PATIENTS–282 men and 244 women aged
20-74 with heterozygous familial hypercholesterolaemia. MAIN OUTCOME
MEASURE–Standardised mortality ratio, all adults in England and Wales
being taken as standard (standardised mortality ratio = 100 for standard
population). RESULTS–The cohort was followed up for 2234 person years
during 1980-9. Fifteen of the 24 deaths were due to coronary heart
disease, giving a standardised mortality ratio of 386 (95% confidence
interval 210 to 639). The excess mortality from this cause was highest
at age 20-39 (standardised mortality ratio 9686; 3670 to 21,800) and
decreased significantly with age. The standardised mortality ratio for
all causes was 183 (117 to 273) and also was highest at age 20-39
(standardised mortality ratio 902; 329 to 1950). There was no
significant difference between men and women. Criteria for measurement
of cholesterol concentration in cardiovascular screening programmes
(family history, presence of myocardial infarction, angina, stroke,
corneal arcus, xanthelasma, obesity, hypertension, diabetes, or any of
these) were present in 78% of patients.
CONCLUSIONS–Familial hypercholesterolaemia is associated
with a substantial excess mortality from coronary heart disease in
young adults but may not be associated with a substantial excess
mortality in older patients. Criteria for selective
measurement of cholesterol concentration in cardiovascular screening
programmes identify about three quarters of patients with the
clinically overt condition.
——————————
phytosterol Bergamonte™ Citrus Bergamia500 mg. Risso Polyphenolic Extract (fruit)
The Bergamot orange (Citrus bergamia) is a yellow-colored citrus
fruit the size of a lemon mainly grown in the southern Calabria region
of Italy. It is distinct from other citrus fruits based on its unique
profile and high concentration of flavonoids and flavonoid glycosides.
Preliminary
cell-based and animal research studies have shown several of these
flavonoids to possess anti-atherosclerotic properties, including the
ability to inhibit LDL oxidation. Some also have structural similarity
to the natural substrate of the HMG-CoA reductase enzyme, which is the
major target of statin drugs. Inhibiting this enzyme’s function serves
to decrease cholesterol synthesis.
A recent study by
Vincenzo Mollace and colleagues in Italy (Fitoterapia, 2011)
investigated the effect of bergamot extract high in polyphenols, in
both rats and humans. In rats with diet-induced hyperlipidemia, 10 and
20 mg/kg of bergamot polyphenols orally administered daily for 30 days
led to significant reductions in total cholesterol, LDL, and
triglycerides, with moderate elevations in HDL cholesterol levels seen
compared to rats fed the hypercholesterolemic diet alone.
The
human study was conducted as a randomized, double-blind,
placebo-controlled trial consisting of 237 patients with high
cholesterol levels (104 patients with isolated hypercholesterolemia/LDL
levels greater than 130 mg/dL) (Group A); 42 patients with elevated
cholesterol and triglycerides (Group B); 59 patients with high
cholesterol, triglycerides, and blood sugar (Group C); and a final group
of 32 patients classified as post–statin therapy who had stopped
simvastatin due to musculoskeletal and liver adverse effects (Group D).
Each of the above groups was divided into three subgroups. One subgroup
received 500 mg of bergamot polyphenols per day; the second received
1000 mg/day; the third group received placebo. The post–statin therapy
group received 1500 mg of bergamot polyphenols per day after a 60-day
statin washout period. All patients were treated for 30 days.
In
aggregate, groups A, B, and C showed an average reduction in total
cholesterol of 21.8% and LDL cholesterol of 24.1% and an increase in
HDL levels of 22.3% with 500 mg/day. The group taking 1000 mg/day of
bergamot polyphenols saw reductions of 29.4% and 36.0% in total
cholesterol and LDL, respectively, while achieving an increase in HDL
levels of 40.1%. All parameters in the placebo group were essentially
unchanged from baseline. In the post-statin group, there was a 25.0%
reduction in total cholesterol, 27.6% decrease in LDL levels, and a
23.8% increase in HDL—with none of the side effects seen earlier with
statin therapy in this group. Based on these results, the bergamot
polyphenols proved to be an effective therapeutic intervention for
elevated cholesterol levels as well as a safe and beneficial alternative
for individuals intolerant to statin drugs.
Hypolipemic and hypoglycaemic activity of bergamot polyphenols:
from animal models to human studies. Mollace V, Sacco I, Janda E,
Malara C, Ventrice D, Colica C, Visalli V, Muscoli S, Ragusa S, Muscoli
C, Rotiroti D, Romeo F. SourceFaculty of Pharmacy, Department of
Pharmacobiological Sciences, University Magna Graecia, Catanzaro,
Italy.
Bergamot juice produces hypolipemic activity in rats though the
mechanism remains unclear. Here we investigated on the effect of
bergamot extract (BPF) in diet-induced hyperlipemia in Wistar rats and
in 237 patients suffering from hyperlipemia either associated or not
with hyperglycaemia. BPF, given orally for 30 days to both rats and
patients, reduces total and LDL cholesterol levels (an effect
accompanied by elevation of cHDL), triglyceride levels and by a
significant decrease in blood glucose. Moreover, BPF inhibited HMG-CoA
reductase activity and enhanced reactive vasodilation thus representing
an efficient phytotherapeutic approach in combating hyperlipemic and
hyperglycaemic disorders.
The NICE guidelines for familial hypercholesterolaemia (FH) are
based on the commonly accepted view that early coronary heart disease
in FH is caused by high cholesterol. 1
Several observations indicate that it is not that simple.
First, studies including only people with FH have shown that both the
prevalence and future cardiovascular disease are independent on their
blood cholesterol level. In one of the studies mean cholesterol was
even lowest in those who had coronary heart disease (CHD). In
accordance, cholesterol lowering by ileal surpass has no effect in
FH, indicating that the small effect obtained with the statins is due
to their pleiotropic effects. Most likely, it is their effect on the
coagulation system, because people with FH may have other genetic
aberrations as well.7
This interpretation fits well with the fact that atherosclerosis
in FH is mainly located to arteries that are exposed to mechanical
forces, while premature atherosclerosis is absent in the cerebral
arteries, even in homozygous FH.
Even more surprising is that according to the The Simon Broome FH
Register Group, the mean life expectancy in FH is as long as for other
people; more die from CHD at a young age, but fewer die from cancer and
other diseases later in life.16 These calculations were based on a
selection of FH people with close relatives, who had died early, and
the authors therefore assumed that the prognosis would have been even
better for unselected individuals. Also, before 1900 their life
expectancy was longer than for the general population, Therefore,
a more appropriate management of FH might be to evaluate the
coagulation system and to find appropriate means to correct possible
abnormalities. People with FH without such abnormalities should also be
told that their high cholesterol is an advantage. The peace of mind
following this information should probably be more beneficial for the
prevention of CHD than any cholesterol lowering measure.
References
1. Wierzbicki AS, Humphries SE, Minhas R; Guideline Development
Group. Familial hypercholesterolaemia: summary of NICE guidance.BMJ
2. Miettinen TA, Gylling H. Mortality and cholesterol metabolism
in familial hypercholesterolemia. Long-term follow-up of 96
patients.Arteriosclerosis 1988;8:163-7.
3. Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and
environmental factors affecting the incidence of coronary artery
disease in heterozygous familial hypercholesterolemia.
4.Ferrieres J, Lambert J, Lussier-Cacan S, Davignon J. Coronary
artery disease in heterozygous familial hypercholesterolemia patients
with the same LDL receptor gene mutation. Circulation 1995; 92:290-5.
5.Kroon AA, Ajubi N, van Asten WN, Stalenhoef AF.The prevalence of
peripheral vascular disease in familial hypercholesterolaemia
6.Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt SE.
Evaluation of coronary risk factors in patients with heterozygous
famlial hypercholesterolema.
7.Jansen AC, van Aalst-Cohen ES, Tanck MW, Cheng S, Fontecha
MR, Li J, et al. Genetic determinants of cardiovascular disease risk in
familial hypercholesterolemia.
8.Koivisto PVI, Leinonen H.Peripheral arterial disease in
heterozygous familial hypercholesterolemia: no difference between
patients with and without partial ileal bypass. Atherosclerosis 1988;70:21-7
9. Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH,
Tegeler CH, et al. Torcetrapib and carotid intima-media thickness.
Lancet 2007;370:153-60.
10. Tremoli E, Folco G, Agradi E, Galli C. Platelet thromboxanes and serum-cholesterol. Lancet 1979;1:107-8.
11.
Schrör K. Platelet reactivity and arachidonic acid metabolism in type
II hyperlipoproteinaemia and its modification by cholesterol-lowering
agents.Eicosanoids 1990; , 67-73.
12. Davì G, Averna M,
Catalano I, Barbagallo C, Ganci A, Notarbartolo A, et al. Increased
thromboxane biosynthesis in type IIa hypercholesterolemia.Circulation
1992:85:1792-8.
13. Sugrue DD and others. Coronary artery
disease and haemostatic variables in heterozygous familial
hypercholesterolaemia. Br Heart J1985;53:265-8.
14. Postiglione
A, Nappi A, Brunetti A, Soricelli A, Rubba P, Gnasso A, et al.Relative
protection from cerebral atherosclerosis of young patients with
homozygous familial hypercholesterolemia. Atherosclerosis 1991;90:23-30.
15.
Rodriguez G, Bertolini S, Nobili F, Arrigo A, Masturzo P, Elicio N, et
al.Regional cerebral blood flow in familial hypercholesterolaemia.
Stroke1994;25:831-6.
16. Neil HA, Hawkins MM, Durrington PN,
Betteridge DJ, Capps NE, Humphries SE, et al. Non-coronary heart disease
mortality and risk of fatal cancer in patients with treated
heterozygous familial hypercholesterolaemia: a prospective registry
study.Atherosclerosis2005;179:293-7.
17. Sijbrands EJ,
Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ.
Mortality over two centuries in large pedigree with familial
hypercholesterolaemia: family tree mortality study.BMJ 2001;322:1019-23.
18. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM 2003;96:927-34.
Angelique
C.M. Jansen; Emily S. van Aalst-Cohen; Michael W.T. Tanck; Suzanne
Cheng; Marcel R. Fontecha; Jia Li; Joep C. Defesche; John J.P.
KasteleinFrom the Departments of Vascular Medicine (A.C.M.J.,
E.S.v.A.-C., J.C.D., J.J.P.K.) and Clinical Epidemiology and
Biostatistics (M.W.T.T.), Academic Medical Center, University of
Amsterdam, the Netherlands; and the Department of Human Genetics (S.C.,
M.R.F., J.L.), Roche Molecular Systems, Inc, Alameda, Calif.
Correspondence to John J.P. Kastelein, Department of Vascular Medicine,
Academic Medical Center, Meibergdreef 9, P.O.Box 22700, room F4-159.2,
1100 DE Amsterdam, the Netherlands.
Objective—
To investigate the contribution of polymorphisms in multiple candidate
genes to cardiovascular disease (CVD) risk in a large cohort of
patients with heterozygous familial hypercholesterolemia (FH).Methods
and Results— We genotyped 1940 FH patients for 65
polymorphisms in 36 candidate genes. During 91.451 person-years, 643
(33.1%) patients had at least 1 cardiovascular event. Multifactorial
Cox survival analysis revealed that the G20210A polymorphism in the prothrombin gene was strongly associated with a significantly increased CVD risk (GA versus GG; P<0.001).
Conclusions— In
a large cohort of FH patients, we found that the G20210A polymorphism
in the prothrombin gene is strongly associated with CVD risk.
Our results constitute a step forward in the unraveling of the
hereditary propensity toward CVD in FH and might lead to better risk
stratification and hence to more tailored therapy for CVD prevention.We
investigated the contribution of 65 polymorphisms in 36 candidate genes
to CVD risk in FH patients and found that the G20210A polymorphism in
the prothrombin gene was associated with CVD risk. Our results
constitute a step forward in the unraveling of the hereditary propensity
toward CVD in FH.
Angiology Volume 60 Number 1 February/March 2009 127-128 # 2009 SAGE Publications 10.1177/0003319708327788
Letter to the Editor.
After the Failure of ENHANCEd Cholesterol Lowering in Familial
Hypercholesterolemia, SEAS of Problems with Ezetimibe by Luca
Mascitelli, MD Uffe Ravnskov, MD, PhD Francesca Pezzetta, MD Ospedale di Tolmezzo Mark R. Goldstein, MD, FACP
Mounting evidence suggests that in familial hypercholesterolemia
neither the incidence3 nor the prevalence4 of cardiovascular disease is
associated with the lipid levels. This striking observation has been
explained by the narrow range of LDL concentrations. 3
The argument is untenable, however, because total and LDL
cholesterol in some individuals with familial hypercholesterolemia may
be more than twice as high as in others. A possible cause of
cardiovascular disease in familial hypercholesterolemia may be inborn
errors of the coagulation system.
1 Whayne TF
Jr. Is there a problem with ezetimibe or just ENHANCEd hype? Angiology.
2008 Sep 15 [Epub ahead of print].2. Pedone C, Carbonin P, Kastelein
JJ, et al. ENHANCE
Investigators.
Simvastatin with or without ezetimibe in familial hypercholesterolemia.
N
Engl J Med. 2008;358:1431-1443.3. Jansen AC, van Aalst-Cohen ES, Tanck
MW, et al.The contribution of classical risk factors to cardiovascular
disease in familial hypercholesterolaemia: data in 2400
patients.
J
Intern Med. 2004;256:482-490.4. de Sauvage Nolting PR, Defesche JC,
Buirma RJ,Hutten BA, Lansberg PJ, Kastelein JJ. Prevalence and
significance of cardiovascular risk factors in a large cohort
of patients with familial hypercholesterolaemia.
J
Intern Med. 2003;253:161-168.5. SugrueDD, Trayner I,ThompsonGR, et
al.Coronary artery disease and haemostatic variables in heterozygous
familial hypercholesterolaemia.
Br Heart J.
1985;53: 265-268.6. Jansen AC, van Aalst-Cohen ES, Tanck MW, et al,
Genetic determinants of cardiovascular disease risk in
familial hypercholesterolemia.
Arterioscler Thromb Vasc
Biol. 2005;25:1475-1481.7. Rossebø AB, Pedersen TR, Boman K, et al. for
the SEAS Investigators. Intensive lipid lowering with simvastatin
and ezetimibe in aortic stenosis.
N Engl J Med. 2008;359:1343-1356.8 Goldstein MR, Mascitelli L,
Pezzetta F. The doubleedged sword of statin immunomodulation. Int J
Cardiol. 2008 May 15 [Epub ahead of print].9. Shepherd J, Blauw GJ,
Murphy MB, et al, and the PROSPER study group. PROspective Study of
Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals
at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet. 2002;360:1623-1630.10. Bradford PG, Awad AB. Phytosterols as anticancer compounds.
Mol Nutr Food Res. 2007;51:161-170.11. Ravnskov U. Re: the association between statins and cancer incidence in a veterans
====================================
J Intern Med. 2004 Dec;256(6):482-90.
The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients.
Jansen AC, van Aalst-Cohen ES, Tanck MW, Trip MD, Lansberg PJ, Liem
AH, van Lennep HW, Sijbrands EJ, Kastelein JJ. Department of Vascular
Medicine, Academic Medical Centre, University of Amsterdam, 1105 AZ
Amsterdam, the Netherlands.
OBJECTIVE: To determine the contribution
of classical risk factors to the development of cardiovascular disease
(CVD) in patients with heterozygous familial hypercholesterolaemia
(FH).DESIGN: A retrospective, multi-centre, cohort study. Extensive
data were collected by scrutinizing medical records and the use of
questionnaires. Multivariate Cox regression was used to study the
relationship between potential risk factors and the occurrence of
CVD.SETTING AND SUBJECTS: We included 2400 FH patients from 27 Dutch
lipid clinics. The diagnosis of FH was based upon the presence of a
low-density lipoprotein receptor mutation or upon strict clinical
criteria.MAIN OUTCOME MEASURES: Cardiovascular mortality and
CVD.RESULTS: During 112.943 person-years, 782 (32.6%) patients had had at least one cardiovascular event. Male
gender (RR 2.82, 95% CI 2.37-3.36), smoking (RR 1.67, 95% CI
1.40-1.99), hypertension (RR 1.36, 95% CI 1.06-1.75), diabetes mellitus
(RR 2.19, 95% CI 1.36-3.54), low HDL-C (RR 1.37, 95% CI 1.15-1.63) and
elevated lipoprotein(a) levels (RR 1.50, 95% CI 1.20-1.79) proved to be
independent CVD risk factors. These six risk factors explained 18.7%
of the variation in the occurrence of CVD.
CONCLUSIONS:
Male
gender, smoking, hypertension, diabetes mellitus, HDL cholesterol and
lipoprotein(a) levels proved to be important risk factors for CVD in FH
patients. In addition to the routine institution of statin
therapy, controlling these factors needs special attention in the
management of this disorder.
————————————
http://www.ncbi.nlm.nih.gov/pubmed/16141286 Clin Chem. 2005 Nov;51(11):2067-73. Epub 2005 Sep 1.
Lipoprotein(a)
is an independent risk factor for cardiovascular disease in
heterozygous familial hypercholesterolemia. Holmes DT, Schick BA,
Humphries KH, Frohlich J. St. Paul’s Hospital Lipid Clinic and the
University of British Columbia Department of Pathology and Laboratory
Medicine, Vancouver, Canada.
Abstract
BACKGROUND: The role of
lipoprotein(a) [Lp(a)] as a predictor of cardiovascular disease (CVD)
in patients with heterozygous familial hypercholesterolemia (HFH) is
unclear. We sought to examine the utility of this lipoprotein as a
predictor of CVD outcomes in the HFH population at our lipid clinic.
METHODS:
This was a retrospective analysis of clinical and laboratory data from
a large multiethnic cohort of HFH patients at a single, large lipid
clinic in Vancouver, Canada.
Three hundred and eighty-eight
patients were diagnosed with possible, probable, or definite HFH by
strict clinical diagnostic criteria. Multivariate Cox regression
analysis was used to study the relationship between several established
CVD risk factors, Lp(a), and the age of first hard CVD event.
RESULTS:
An Lp(a) concentration of 800 units/L (560 mg/L) or higher was a
significant independent risk factor for CVD outcomes [hazard ratio (HR)
= 2.59; 95% confidence interval (CI), 1.53-4.39; P < 0.001].
Other significant risk factors were
male sex [HR =
3.19
(1.79-5.69); P < 0.001] and ratio of total to HDL-cholesterol [1.18
(1.07-1.30); P = 0.001]. A previous history of smoking or hypertension
each produced HRs consistent with increased CVD risk [HR = 1.55
(0.92-2.61) and 1.57 (0.90-2.74), respectively], but neither reached
statistical significance (both P = 0.10).
LDL-cholesterol was not an independent predictor of CVD risk [HR = 0.85
(0.0.71-1.01); P = 0.07], nor was survival affected by the subcategory
of HFH diagnosis (i.e., possible vs probable vs definite HFH).
CONCLUSION: Lp(a) is an independent predictor of CVD risk in a multiethnic HFH population.
——————–
http://www.ncbi.nlm.nih.gov/pubmed/15547022 Heart. 2004 Dec;90(12):1431-7.
Established and emerging coronary risk factors in patients with
heterozygous familial hypercholesterolaemia. Neil HA, Seagroatt V,
Betteridge DJ, Cooper MP, Durrington PN, Miller JP, Seed M, Naoumova RP,
Thompson GR, Huxley R, Humphries SE. Division of Public Health &
Primary Health Care, Institute of Health Sciences, University of Oxford,
Old Road, Headington, Oxford OX3 7LF, UK.
Abstract
OBJECTIVES: To assess the clinical and biochemical factors associated
with inter-individual variation in susceptibility to coronary artery
disease (CAD) in treated heterozygous familial hypercholesterolaemia.
DESIGN: A cross sectional study was conducted of
410 patients recruited from six lipid clinics in the UK.
RESULTS:
CAD was documented in 104 of the 211 men and in 55 of the 199 women
with mean ages of onset of 43.1 and 46.5 years, respectively. CAD was
significantly more common in men (49% v 28%, p < 0.001) and in
patients who had
smoked cigarettes versus patients who
had never smoked (51% v 28%, p < 0.001). After adjusting for age,
sex, and current smoking status, there were no significant differences
between patients with or without CAD in lipoprotein(a), homocysteine,
fibrinogen, plasminogen activator inhibitor-1, white blood cell count,
body mass index, glucose, triglyceride or total cholesterol. However,
high density lipoprotein (HDL) cholesterol concentrations were
significantly lower in those with CAD (6%, 95% confidence interval (CI)
1% to 11%, p = 0.03) and this difference was greater in women than men
(12% v 2%, p = 0.041).
CONCLUSIONS: These results indicate that
emerging coronary risk factors appear not to be associated with CAD in
adults with treated familial hypercholesterolaemia, but the
strong
association with smoking suggests that patients should be identified
early in childhood and discouraged from ever starting to smoke.
———————-
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2563208/ J Med Genet. 2006 December; 43(12): 943–949.
Genetic
causes of familial hypercholesterolaemia in patients in the UK:
relation to plasma lipid levels and coronary heart disease risk. S E
Humphries, R A Whittall, C S Hubbart, S Maplebeck, J A Cooper, A K
Soutar, R Naoumova, G R Thompson, M Seed, P N Durrington, J P Miller, D J
B Betteridge, and H A W Neil, for the Simon Broome Familial
Hyperlipidaemia Register Group and Scientific Steering Committee S E
Humphries, R A Whittall, C S Hubbart, S Maplebeck, J A Cooper, Centre
for Cardiovascular Genetics, British Heart Foundation Laboratories,
Royal Free and University College London Medical School, London, UKA K
Soutar, R Naoumova, G R Thompson, Medical Research Council Clinical
Sciences Centre, Imperial College Faculty of Medicine, Hammersmith
Hospital, London, UK
—————————————-
http://www.atherosclerosis-journal.com/article/S0021-9150(04)00544-1/abstract Atherosclerosis Volume 179, Issue 2 , Pages 293-297, April 2005
Non-coronary
heart disease mortality and risk of fatal cancer in patients with
treated heterozygous familial hypercholesterolaemia: a prospective
registry study
H.A.W. Neil et al.
The prognosis from coronary
heart disease (CHD) for patients with heterozygous familial
hypercholesterolaemia has improved substantially since the introduction
of HMG Co-A reductase inhibitors
(statins), but the
effect of lipid-lowering drug therapy combined with dietary and life
style advice on non-coronary mortality and the risk of fatal cancer is
unclear.
Methods:The cohort of
2871 patients was recruited from 21 outpatient lipid clinics in the UK from
1980 to 1998 and was followed for
22,992 person-years.
The standardised mortality ratio (SMR) was calculated from the ratio
of the number of deaths observed to the number expected in the general
population of England and Wales.
Results:There were
169 deaths, including 102 (
60.4%) from CHD, and 32 (18.9%) from cancer.
The SMR for CHD was 2.5-fold higher than in the general population
(95% CI 2.1, 3.1), but the all-cause SMR was not increased (1.1, 95% CI
0.9, 1.3) and non-coronary mortality was significantly lower in men
(0.5, 95% CI 0.3, 0.7) and women (0.6, 95% CI 0.4, 0.9).
The
SMR for all cancers was significantly reduced (0.6, 95% CI 0.4, 0.8)
with an 80% reduction in fatal cancers of the respiratory and
intra-thoracic organs and a non-significant reduction in fatal cancers
of the genitourinary and digestive organs.
Conclusions:Although
the study cannot exclude the possibility that statins have anti-cancer
activity, the results strongly suggest that giving advice to consume a
healthy diet, increase physical activity and stop smoking is
associated with a substantial reduction in mortality from cancer.
——————————————————-
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC31037/?tool=pubmed
BMJ. 2001 April 28; 322(7293): 1019–1023.
Mortality
over two centuries in large pedigree with familial
hypercholesterolaemia: family tree mortality study.Sijbrands EJ,
Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ.
Department of Vascular Medicine and General Internal Medicine, Academic
Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease.
Design
Family tree mortality study.Setting Large pedigree in Netherlands
traced back to a single pair of ancestors in the 19th century.Subjects
All members of pedigree aged over 20 years with 0.5 probability of
carrying a mutation for familial hypercholesterolaemia.Main outcome
measure All cause mortality.
Results A total of
70 deaths took place among 250 people analysed for 6950 person years.
Mortality was not increased in carriers of the mutation during the 19th and early 20th century;
it rose after 1915, reached its maximum between 1935 and 1964
(standardised mortality ratio 1.78, 95% confidence interval 1.13 to
2.76; P=0.003), and fell thereafter. Mortality differed significantly
between two branches of the pedigree (relative risk 3.26, 95% confidence
interval 1.74 to 6.11; P=0.001).
Conclusions
Risk of death varies significantly among patients with familial hypercholesterolaemia.
This large variability over time and between branches of the pedigree
points to a strong interaction with environmental factors. Future
research is required to identify patients with familial
hypercholesterolaemia who are at extreme risk and need early and
vigorous preventive measures.
———————————————
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583391/?tool=pubmedhttp://www.ncbi.nlm.nih.gov/pubmed/19001495 free full
BMJ. 2008 Nov 11;337:a2423.
Efficacy of statins in familial hypercholesterolaemia: a long term
cohort study. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC,
Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ,
Sijbrands EJ. SourceDepartment of Internal Medicine, Erasmus
University Medical Centre, PO box 2040, 3000 CA
Rotterdam, Netherlands.
Abstract
OBJECTIVE: To determine the efficacy of statin treatment on risk of
coronary heart disease in patients with familial hypercholesterolaemia.
DESIGN: Cohort study with a mean follow-up of 8.5 years.
SETTING: 27 outpatient lipid clinics.
SUBJECTS: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990.
MAIN OUTCOME MEASURES: Risk of coronary heart disease in treated and
“untreated” (delay in starting statin treatment) patients compared with a
Cox regression model in which statin use was a time dependent
variable.
RESULTS: In January 1990, 413 (21%) of the patients had
started statin treatment, and during follow-up another 1294 patients
(66%) started after a mean delay of 4.3 years. Most patients received
simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily).
We observed an overall risk reduction of 76% (hazard ratio 0.24 (95%
confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of
myocardial infarction in these statin treated patients was not
significantly greater than that in an age-matched sample from the
general population (hazard ration 1.44 (0.80 to 2.60), P=0.23).
CONCLUSION:
Lower statin doses than those currently advised reduced the risk of
coronary heart disease to a greater extent than anticipated in patients
with familial hypercholesterolaemia. With statin treatment, such
patients no longer have a risk of myocardial infarction significantly
different from that of the general population.
We finally
compared the risk of myocardial infarction in patients with familial
hypercholesterolaemia who were older than 55 years (n=261, 64 men) with
that in 1975 people in a subgroup of the participants in the Rotterdam
study. The mean age in both subgroups was 61.6 years and both had
24.5% men as a result of stratified selection from the Rotterdam study.
The absolute risk of myocardial infarction was 6.7/1000 person years
in our statin treated patients, 60.5/1000 person years in our untreated
patients, and 4.1/1000 person years in the sample from the Rotterdam
study.
Event-free survival of our statin treated patients was
not significantly different from that of the Rotterdam study sample
(log rank test P=0.07), whereas our untreated patients clearly had a
higher risk of coronary heart disease (log rank test P<0.001) (fig
4​4).). After adjustment for year of birth and sex, the
point estimate of risk of myocardial infarction in our treated patients
with familial hypercholesterolaemia was higher than the risk in the
subgroup of the Rotterdam study, but this was not significant (hazard
ratio 1.44 (0.80 to 2.60), P=0.23), whereas the risk in our untreated
patients was 8.7 times higher (hazard ratio 8.69 (4.77 to 15.82),
P<0.001).
We report here that relatively modest doses of
statins reduced the risk of coronary heart disease by about 80% in
patients with familial hypercholesterolaemia. This is a much more
pronounced reduction than was anticipated based on secular trends in
earlier studies.7 8
We also observed that statin treated
patients older than 55 years had a risk of myocardial infarction
approaching that of the general population. Finally, men and women experienced similar risk reductions in our study.
———————-
http://www.endocrinologyrounds.ca/crus/118-076%20English.pdf
Familial Hypercholesterolemia: Why every endocrinologist should know about PCSK9 B Y PHI L I P W. CONNE L LY, PHD
Familial hypercholesterolemia
———————————–
Cholesterol Freatment Trialists’ (CTT) Collaborators. 2005
http://www.ncbi.nlm.nih.gov/pubmed/16214597?dopt=Abstract
Cholesterol Freatment Trialists’ (CTT) Collaborators. Efficacy and
safety of cholesterol-lowering treatment: prospective meta-analysis of
data from 90,056 participants in 14 randomised trials of statins. Lancet
2005;366:1267-1278.
Lancet. 2005 Oct 8;366(9493):1267-78. .
Efficacy and safety of cholesterol-lowering treatment: prospective
meta-analysis of data from 90,056 participants in 14 randomised trials
of statins.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G,
Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R;
Cholesterol Treatment Trialists’ (CTT) Collaborators.
Results of
previous randomised trials have shown that interventions that lower
LDL cholesterol concentrations can significantly reduce the incidence
of coronary heart disease (CHD) and other major vascular events in a
wide range of individuals. But each separate trial has limited power to
assess particular outcomes or particular categories of participant.
METHODS:A prospective meta-analysis of data from 90,056 individuals in
14 randomised trials of statins was done. Weighted estimates were
obtained of effects on different clinical outcomes per 1.0 mmol/L
reduction in LDL cholesterol.
FINDINGS:During a mean of 5 years,
there were 8186 deaths, 14,348 individuals had major vascular events,
and 5103 developed cancer. Mean LDL cholesterol differences at 1 year
ranged from 0.35 mmol/L to 1.77 mmol/L (mean 1.09) in these trials.
There was a 12% proportional reduction in all-cause mortality per
mmol/L reduction in LDL cholesterol (rate ratio [RR] 0.88, 95% CI
0.84-0.91; p<0.0001). This reflected a 19% reduction in coronary
mortality (0.81, 0.76-0.85; p<0.0001), and non-significant
reductions in non-coronary vascular mortality (0.93, 0.83-1.03; p=0.2)
and non-vascular mortality (0.95, 0.90-1.01; p=0.1). There were
corresponding reductions in myocardial infarction or coronary death
(0.77, 0.74-0.80; p<0.0001), in the need for coronary
revascularisation (0.76, 0.73-0.80; p<0.0001), in fatal or non-fatal
stroke (0.83, 0.78-0.88; p<0.0001), and, combining these, of 21% in
any such major vascular event (0.79, 0.77-0.81; p<0.0001). The
proportional reduction in major vascular events differed significantly
(p<0.0001) according to the absolute reduction in LDL cholesterol
achieved, but not otherwise. These benefits were significant within the
first year, but were greater in subsequent years. Taking all years
together, the overall reduction of about one fifth per mmol/L LDL
cholesterol reduction translated into 48 (95% CI 39-57) fewer
participants having major vascular events per 1000 among those with
pre-existing CHD at baseline, compared with 25 (19-31) per 1000 among
participants with no such history. There was no evidence that statins
increased the incidence of cancer overall (1.00, 0.95-1.06; p=0.9) or at
any particular site.
INTERPRETATION: Statin therapy can safely
reduce the 5-year incidence of major coronary events, coronary
revascularisation, and stroke by about one fifth per mmol/L reduction
in LDL cholesterol, largely irrespective of the initial lipid profile
or other presenting characteristics. The absolute benefit relates
chiefly to an individual’s absolute risk of such events and to the
absolute reduction in LDL cholesterol achieved. These findings
reinforce the need to consider prolonged statin treatment with
substantial LDL cholesterol reductions in all patients at high risk of
any type of major vascular event.
Mohrschladt 2004
http://www.ncbi.nlm.nih.gov/pubmed/15019543/ Atherosclerosis. 2004 Feb;172(2):329-35.
Cardiovascular disease and mortality in statin-treated patients with
familial hypercholesterolemia. Mohrschladt MF, Westendorp RG, Gevers
Leuven JA, Smelt AH.
Source Department of General Internal Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 RC
Leiden, The Netherlands.
Patients
with familial hypercholesterolemia (FH) are at an increased risk of
premature cardiovascular disease (CVD). The benefits of statin therapy
are not well known since no placebo controlled studies have been
performed in these patients. The aim of this study was to determine the
CVD event and mortality risk in statin-treated patients with FH.
A total of 345 FH patients were followed prospectively for 8 years. Mortality from CVD was compared to that of the general population.
The
absolute risk of CVD in patients without a previous history of CVD was
3% per year for men and 1.6% for women. Mortality from CVD in patients
without a previous history was 1.4-fold (95% CI = 0.6-3.3) increased
and ischaemic heart disease (IHD) mortality was 2.6-fold (95% CI =
1.1-6.3) higher compared to the general population.
This mortality risk was highest in patients aged 40-59 years.
Female
FH patients had no increased CVD or IHD mortality risk. Over a period
of 8 years the event risk of patients with a history of CVD was almost
30% per year under age 40 years and 15% in patients aged 60 years and
over. When compared to the general population, mortality from other
causes than CVD was lower for patients with FH, the relative risks not
reaching statistical significance. The relative risk of mortality from
all causes was 1.5 (P < 0.05) for men and 1.0 for women. In
conclusion, male patients with FH, treated from middle-age with statins
remain at an increased risk of developing CVD.
———-
Coronary Calcium Score in FHC
http://www.ncbi.nlm.nih.gov/pubmed/21565855 Heart. 2011 Jul;97(14):1151-7. doi: 10.1136/hrt.2010.220699. Epub 2011 May 12.
CT coronary plaque burden in asymptomatic patients with familial hypercholesterolaemia.
Neefjes LA, Ten Kate GJ, Rossi A, Galema-Boers AJ, Langendonk JG,
Weustink AC, Moelker A, Nieman K, Mollet NR, Krestin GP, Sijbrands EJ,
de Feyter PJ.
SourceDepartment of Radiology and Cardiology, Erasmus
Medical Center Rotterdam, CA, Rotterdam, The Netherlands.OBJECTIVE:To
determine the calcium score and coronary plaque burden in asymptomatic
statin-treated patients with heterozygous familial
hypercholesterolaemia (FH) compared with a control group of patients
with low probability of coronary artery disease, having non-anginal
chest pain, using CT.
DESIGN, SETTING AND PATIENTS:101 asymptomatic
patients with FH (mean age 53 ± 7 years; 62 men) and 126 patients with
non-anginal chest pain (mean age 56 ± 7 years; 80 men) underwent CT
calcium scoring and CT coronary angiography. All patients with FH were
treated with statins during a period of 10 ± 8 years before CT. The
coronary calcium score and plaque burden were determined and compared
between the two patient groups.
RESULTS:The median total calcium
score was significantly higher in patients with FH (Agatston score =
87, IQR 5-367) than in patients with non-anginal chest pain (Agatston
score = 7, IQR 0-125; p < 0.001). The overall coronary plaque burden
was significantly higher in patients with FH (p < 0.01). Male
patients with FH, whose low-density lipoprotein cholesterol levels were
reduced by statins below 3.0 mmol/l, had significantly less coronary
calcium (p < 0.01) and plaque burden (p = 0.02).
CONCLUSION:The coronary plaque burden is high in asymptomatic middle-aged patients with FH despite intense statin treatment.
http://www.ncbi.nlm.nih.gov/pubmed/22460051 Atherosclerosis. 2012 Jun;222(2):468-72. doi: 10.1016/j.atherosclerosis.2012.02.043. Epub 2012 Mar 7.
Detection of subclinical atherosclerosis in familial hypercholesterolemia using non-invasive imaging modalities.
Caballero P, Alonso R, Rosado P, Mata N, Fernández-Friera L, Jiménez-Borreguero LJ, Badimon L, Mata P.
Source Department of Radiology, Hospital de la Princesa, Madrid,
Spain.To investigate the extent of subclinical atherosclerosis in
asymptomatic familial hypercholesterolemia (FH) patients using
non-invasive images techniques.
PATIENTS, METHODS AND RESULTS:The
atherosclerotic burden of 36 molecularly defined FH patients (18 males,
45.7±10.9 years) without evidence of cardiovascular disease receiving
lipid-lowering treatment and 19 (47.8±11.3 years) controls was
investigated. Descending thoracic aorta magnetic resonance imaging
(MRI) was performed in a 1.5 T equipment with T1 and T2 sequences to
characterize atherosclerotic plaques and to measure aortic wall
volumen. Carotid intima-media thickness (cIMT) and presence of plaques
were measured using B-mode carotid ultrasound. Mean aortic wall
volumen, cIMT and atherosclerotic plaques in aorta were significantly
higher in FH cases (P<0.001). A significant correlation between
aortic wall volume and cIMT was observed (P<0.01). Aortic MRI
detected plaques in 94% and carotid ultrasound in 14% of cases.
Lipid-rich plaques were observed only in FH cases (33%) and were
associated with family history of premature coronary artery disease
(P<0.05).
CONCLUSIONS:Asymptomatic middle-aged FH patients have
significantly higher atherosclerotic burden than controls. cIMT has
shown a significant correlation with aortic wall volume and MRI allowed
the detection of lipid-rich plaques in FH subjects that were
associated with family history of premature coronary artery disease.
http://www.ncbi.nlm.nih.gov/pubmed/22018443 Atherosclerosis. 2011 Dec;219(2):721-7. doi: 10.1016/j.atherosclerosis.2011.09.052. Epub 2011 Oct 8.
Accelerated subclinical coronary atherosclerosis in patients with familial hypercholesterolemia.
Neefjes LA, Ten Kate GJ, Alexia R, Nieman K, Galema-Boers AJ,
Langendonk JG, Weustink AC, Mollet NR, Sijbrands EJ, Krestin GP, de
Feyter PJ.
Source Department of Radiology, Erasmus Medical Center,
Rotterdam, The Netherlands.We determined the extent, severity,
distribution and type of coronary plaques in cardiac asymptomatic
patients with familial hypercholesterolemia (FH) using computed
tomography (CT).
BACKGROUND:FH patients have accelerated progression
of coronary artery disease (CAD) with earlier major adverse cardiac
events. Non-invasive CT coronary angiography (CTCA) allows assessing
the coronary plaque burden in asymptomatic patients with FH.
MATERIALS AND METHODS:A total of 140 asymptomatic statin treated FH
patients (90 men; mean age 52 ± 8 years) underwent CT calcium scoring
(Agatston) and CTCA using a Dual Source CT scanner with a clinical
follow-up of 29 ± 8 months. The extent, severity (obstructive or
non-obstructive plaque based on >50% or <50% lumen diameter
reduction), distribution and type (calcified, non-calcified, or mixed)
of coronary plaque were evaluated.
RESULTS:The calcium score was 0
in 28 (21%) of the patients. In 16% of the patients there was no
CT-evidence of any CAD while 24% had obstructive disease. In total 775
plaques were detected with CT coronary angiography, of which 11% were
obstructive. Fifty four percent of all plaques were calcified, 25%
non-calcified and 21% mixed. The CAD extent was related to gender,
treated HDL-cholesterol and treated LDL-cholesterol levels. There was a
low incidence of cardiac events and no cardiac death occurred during
follow-up.
CONCLUSION:Development of CAD is accelerated in
intensively treated male and female FH patients. The extent of CAD is
related to gender and cholesterol levels and ranges from absence of
plaque in one out of 6 patients to extensive CAD with plaque causing
>50% lumen obstruction in almost a quarter of patients with FH.
http://www.ncbi.nlm.nih.gov/pubmed/20980000 Atherosclerosis. 2010 Dec;213(2):486-91. doi: 10.1016/j.atherosclerosis.2010.10.001. Epub 2010 Oct 25.
Evaluation of subclinical atherosclerosis by computed tomography
coronary angiography and its association with risk factors in familial
hypercholesterolemia.
Miname MH, Ribeiro MS 2nd, Parga Filho J, Avila LF, Bortolotto LA, Martinez LR, Rochitte CE, Santos RD.
Source Lipid Clinic Heart Institute (InCor), University of São Paulo,
Medical School Hospital, São Paulo, Brazil.Increasing age and
cholesterol levels, male gender, and family history of early coronary
heart disease (CHD) are associated with early onset of CHD in familial
hypercholesterolemia (FH).
OBJECTIVE:Assess subclinical
atherosclerosis by computed tomography coronary angiography (CTCA) and
its association with clinical and laboratorial parameters in
asymptomatic FH subjects.
METHODS:102 FH subjects (36% male, 45 ± 13
years, LDL-c 280 ± 54 mg/dL) and 35 controls (40% male, 46 ± 12 years,
LDL-c 103 ± 18 mg/dL) were submitted to CTCA. Plaques were divided
into calcified, mixed and non-calcified; luminal stenosis was
characterized as >50% obstruction.
RESULTS:FH had a greater
atherosclerotic burden represented by higher number of patients with:
plaques (48% vs. 14%, p=0.0005), stenosis (19% vs. 3%, p=0.015),
segments with plaques (2.05 ± 2.85 vs.0.43 ± 1.33, p=0.0016) and
calcium scores (55 ± 129 vs. 38 ± 140, p=0.0028). After multivariate
analysis, determinants of plaque presence were increasing age (OR=2.06,
for age change of 10 years, CI95%: 1.38-3.07, p<0.001) and total
cholesterol (OR=1.86, for cholesterol change by 1 standard deviation,
CI95%: 1.09-3.15, p=0.027). Coronary calcium score was associated with
the presence of stenosis (OR=1.54; CI95%: 1.27-1.86, p<0.001, for
doubling the calcium score). Male gender was directly associated with
the presence of non-calcified plaques (OR: 15.45, CI95% 1.72-138.23,
p=0.014) and inversely with calcified plaques (OR=0.21, CI95%:
0.05-0.84, p=0.027). Family history of early CHD was associated with
the presence of mixed plaques (OR=4.90, CI95%: 1.32-18.21, p=0.018).
CONCLUSIONS:
Patients
with FH had an increased burden of coronary atherosclerosis by CTCA.
The burden of atherosclerosis and individual plaque subtypes differed
with the presence of other associated risk factors, with age and
cholesterol being most important. A coronary calcium score of zero
ruled out obstructive disease in this higher risk population.
http://www.ncbi.nlm.nih.gov/pubmed/23340035 Am J Cardiol. 2013 Apr 1;111(7):955-61.
Coronary computed tomographic angiographic findings in asymptomatic
patients with heterozygous familial hypercholesterolemia and null allele
low-density lipoprotein receptor mutations.
Viladés Medel D, Leta
Petracca R, Carreras Costa F, Cardona Olle M, Barros Membrilla A,
Hidalgo Perez JA, Pujadas Olano S, Alomar Serrallach X, Franco Peral M,
Pons-Lladó G.
Source Cardiac Imaging Unit, Cardiology Department, Universitat Autònoma de Barcelona, Barcelona, Spain.
Heterozygous
familial hypercholesterolemia (HeFH) can be associated with early
coronary artery disease (CAD) in asymptomatic patients. The objectives
of the present study were to assess the prevalence and magnitude of
subclinical CAD in patients with HeFH using coronary computed
tomographic angiography (CCTA) and to determine the clinical and
genetic profile of those at the greatest risk of CAD. The study
included 50 consecutive patients with HeFH diagnosed according to the
Dutch Lipid Clinic Network criteria and a control group of 70 healthy
subjects. The findings from CCTA for the patients with HeFH were
compared with those from the control group, who had been referred for
CCTA as a part of a preventive medical examination. In 82% of the
patients with HeFH, genetic DNA was screened for low-density lipoprotein
receptor (LDLR) gene mutations using a microarray. CCTA revealed a
significantly greater Agatston calcium score in the study group than in
the control group (260 vs 46; p = 0.002). The prevalence of CAD in the
patients with HeFH was 48%. It was significant in 26%, involving mainly
the proximal segments of the coronary arteries. In the control group,
the prevalence of CAD was 33% and was significant in 5% (p <0.05 for
prevalence and severity of CAD compared to patients with HeFH). In
those with HeFH, increased age, null allele LDLR mutations, and low
high-density lipoprotein blood levels at diagnosis showed a
statistically significant association with CAD (p <0.05). In
conclusion, patients with HeFH present with a greater prevalence,
extension, and severity of subclinical CAD than the general population.
Increased age, low high-density lipoprotein levels, and LDLR null
allele mutations are related to the occurrence of CAD. CCTA has emerged
as a useful technique for the screening of subclinical CAD in patients
with HeFH.
——————————–
http://www.ncbi.nlm.nih.gov/pubmed/3941501 JAMA. 1986 Jan 10;255(2):219-24.
Evidence that men with familial hypercholesterolemia can avoid early
coronary death. An analysis of 77 gene carriers in four Utah pedigrees.
Williams RR, Hasstedt SJ, Wilson DE, Ash KO, Yanowitz FF, Reiber GE, Kuida H.
Abstract
To
study the genetic influence on serum cholesterol levels and early
coronary heart disease, 1,134 individuals were screened from 18 Utah
pedigrees. In most pedigrees, serum cholesterol appeared to be a purely
polygenic trait, with 54% heritability. In four pedigrees with
dominant familial hypercholesterolemia, male heterozygotes had a mean
serum cholesterol level of 352 mg/dL, myocardial infarction at an
average age of 42 years, and coronary death at an average age of 45
years. An informative pedigree structure allowed the identification of
four ancestral males born before 1880 who carried this lethal gene and
survived to ages 62, 68, 72, and 81 years. This suggests that some
healthy life-style factors protected these men against the expression of
a gene that has led to coronary disease by age 45 years in all of
their heterozygous great-grandsons. One heterozygote showed a drop in
serum cholesterol level from 426 to 248 mg/dL, with strict adherence to
a low-fat diet without drugs. These observations should help encourage
physicians to try harder to identify and help such individuals.
http://circ.ahajournals.org/content/92/3/290.longhttp://www.ncbi.nlm.nih.gov/pubmed/7634440 Circulation. 1995 Aug 1;92(3):290-5.
Coronary artery disease in heterozygous familial hypercholesterolemia patients with the same LDL receptor gene mutation.
Ferrières J, Lambert J, Lussier-Cacan S, Davignon J.
SourceDépartement de médecine sociale et préventive, Faculté de Médecine, Université de Montréal, Quebec, Canada.
Abstract
BACKGROUND:Familial hypercholesterolemia (FH), an autosomal codominant
disease, is characterized by high levels of LDL cholesterol and a high
incidence of coronary artery disease (CAD). To date, genetic
heterogeneity has hindered the proper assessment of the relation between
risk factors and CAD in FH patients.
METHODS AND RESULTS:We
studied the association between CAD and common risk factors in a sample
of 263 French Canadian FH patients (147 women, 116 men) carrying the
same > 10-kb deletion of the LDL receptor gene. Thirty-five women
and 54 men had CAD. The mean age of onset of CAD was 45.6 +/- 12.7
years in women and 38.8 +/- 9.4 years in men. Multiple logistic
regression analyses were performed to test the association between CAD
and age, tendon xanthomas, cigarette smoking, hypertension, diabetes
mellitus, apolipoprotein E polymorphism, total plasma cholesterol,
triglycerides, VLDL cholesterol, LDL cholesterol, HDL cholesterol, and
lipoprotein(a) [Lp(a)]. In FH women, significant multivariate
predictors were age (odds ratio, 1.10 for 1 year; P < .0001), VLDL
cholesterol (odds ratio, 3.85 for 1 natural log unit; P < .002), and
LDL cholesterol (odds ratio, 1.42 for 1 mmol/L; P < .02). In FH
men, age (odds ratio, 1.08 for 1 year; P < .0001) and HDL
cholesterol (odds ratio, 0.14 for 1 mmol/L; P = .05) were significant
predictors of disease. Lp(a) was not a significant predictor in
univariate or multivariate analyses.
CONCLUSIONS:This study suggests
that increased risk of CAD in FH is not solely due to elevated LDL
cholesterol levels and demonstrates a sex-specific lipoprotein
influence on CAD in a large sample of FH patients carrying the same LDL
receptor gene defect
Epub 2005 May 5.
Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia.
Jansen AC, van Aalst-Cohen ES, Tanck MW, Cheng S, Fontecha MR, Li J, Defesche JC, Kastelein JJ.
Source Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Abstract OBJECTIVE: To investigate the contribution of polymorphisms
in multiple candidate genes to cardiovascular disease (CVD) risk in a
large cohort of patients with heterozygous familial hypercholesterolemia
(FH).
METHODS AND RESULTS: We genotyped 1940 FH patients for 65
polymorphisms in 36 candidate genes. During 91.451 person-years, 643
(33.1%) patients had at least 1 cardiovascular event. Multifactorial
Cox survival analysis revealed that the G20210A polymorphism in the
prothrombin gene was strongly associated with a significantly increased
CVD risk (GA versus GG; P<0.001).
CONCLUSIONS: In a large cohort of FH patients,
we found that the G20210A polymorphism in the prothrombin gene is
strongly associated with CVD risk. Our results constitute a step
forward in the unraveling of the hereditary propensity toward CVD in FH
and might lead to better risk stratification and hence to more
tailored therapy for CVD prevention.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC481754/ Br Heart J. 1985 Mar;53(3):265-8.
Coronary artery disease and haemostatic variables in heterozygous familial hypercholesterolaemia.
Sugrue DD, Trayner I, Thompson GR, Vere VJ, Dimeson J, Stirling Y, Meade TW.
Abstract Haemostatic variables were measured in 61 patients with
heterozygous familial hypercholesterolaemia, 32 of whom had evidence of
coronary heart disease. Age adjusted mean concentrations of plasma
fibrinogen and factor VIII were significantly higher in these patients
than in the 29 patients without coronary heart disease, but there were
no significant differences in serum lipid concentrations between the two
groups. Comparisons in 30 patients taking and not taking lipid
lowering drugs showed lower values for low density lipoprotein
cholesterol, high density lipoprotein cholesterol and antithrombin III,
and a higher high density lipoprotein ratio while receiving treatment.
The results suggest that hypercoagulability may play a role in the
pathogenesis of coronary heart disease in patients with familial
hypercholesterolaemia.
http://www.ncbi.nlm.nih.gov/pubmed/9920511
Atherosclerosis. 1999 Jan;142(1):105-12.
Mortality in treated heterozygous familial hypercholesterolaemia:
implications for clinical management. Scientific Steering Committee on
behalf of the Simon Broome Register Group. [No authors listed] Abstract
Clinical
management of heterozygous familial hypercholesterolaemia is largely
based on evidence from a small number of observational studies and
extrapolation from the results of clinical trials of lipid-lowering in
patients with polygenic hypercholesterolaemia The objectives of this
study were (i) to determine the absolute and relative mortality of
patients with treated heterozygous familial hypercholesterolaemia, (ii)
to estimate the effect of changes in treatment efficacy on mortality
trends over time, and (iii) to examine the implications of these
findings for patient management. A cohort of 605 men and 580 women aged
20-79 years with heterozyous familial hypercholesterolaemia were
recruited from 21 out-patient lipid clinics in the UK. Patients were
followed prospectively from 1980 to 1995 for 8770 person-years. Absolute
mortality was calculated, and relative risk was expressed as the ratio
of the number of observed deaths to the number expected in the general
population of England and Wales. Forty six of the 73 deaths were due
to coronary heart disease. In women aged 20-39, despite treatment, the
relative risk of a fatal coronary event was increased 125-fold (95%
confidence intervals 15-451) and the annual coronary mortality was
0.17%. In men aged 20-39 the relative risk was increased 48-fold
(17-105) and the annual coronary mortality was 0.46%. The relative risk
decreased with age but the absolute risk increased. For men and women
aged 60-79, the annual coronary mortality was 1.1% representing a
significant excess mortality for women (relative risk 2.6, 1.3-4.5) but
not for men (RR 1.1, 0.5-2.3). Non-coronary mortality was not increased
at any age (RR for all ages 0.68, 0.45-0.99). There was a decline in
the relative risk for coronary mortality in patients aged 20-59 from an
eight-fold (4.8-7.2) increased risk before 1992 to 3.7 (1.6-7.2.)
thereafter (P=0.08). The results suggest that the prognosis for patients
with heterozygous familial hypercholesterolaemia has improved with the
introduction of more effective treatment, and that lipid-lowering
therapy is not associated with increased non-coronary mortality. These
findings and the excess coronary mortality observed suggest that all
affected adult men and post-menopausal women should be treated with
HMG-CoA reductase inhibitors.
Benefits of high cholesterol
‘
http://www.ravnskov.nu/the%20benefits%20of%20high%20C.htm
http://www.ncbi.nlm.nih.gov/pubmed/20952373
Age Ageing. 2010 Nov;39(6):674-80. doi: 10.1093/ageing/afq129. Epub
2010 Oct 14. Lipid-lowering treatment to the end? A review of
observational studies and RCTs on cholesterol and mortality in 80+-year
olds. Petersen LK, Christensen K, Kragstrup J. Source Research Unit of
Epidemiology, Danish Aging Research Center, University of Southern
Denmark, Odense, Denmark. Abstract
People aged 80 or older are
the fastest growing population in high-income countries. One of the
most common causes of death among the elderly is the cardiovascular
disease (CVD). Lipid-lowering treatment is common, e.g. one-third of
75-84-year-old Swedes are treated with statins. The assumption that
hypercholesterolaemia is a risk factor at the highest ages seems to be
based on extrapolation from younger adults. A review of observational
studies shows a trend where all-cause mortality was highest when total
cholesterol (TC) was lowest (‘a reverse J-shaped’ association between
TC and all-cause mortality). Low TC (<5.5 mmol/l) is associated with
the highest mortality rate in 80+-year olds. No clear optimal level of
TC was identified. A review of the few randomised controlled trials
including 80+-year olds did not provide evidence of an effect of
lipid-lowering treatment on total mortality in 80+-year-old people.
There is not sufficient data to recommend anything regarding initiation
or continuation of lipid-lowering treatment for the population aged
80+, with known CVD, and it is even possible that statins may increase
all-cause mortality in this group of elderly individuals without CVD.
Disclaimer click here:
http://www.drdach.com/wst_page20.html
The
reader is advised to discuss the comments on these pages with his/her
personal physicians and to only act upon the advice of his/her personal
physician. Also note that concerning an answer which appears as an
electronically posted question, I am NOT creating a physician — patient
relationship. Although identities will remain confidential as much as
possible, as I can not control the media,
I can not take responsibility for any breaches of confidentiality that may occur.
Link to this article:
http://wp.me/p3gFbV-tl
Copyright
(c) 2009-2013 Jeffrey Dach MD All Rights Reserved. This article may be
reproduced on the internet without permission, provided there is a
link to this page and proper credit is given.
FAIR USE NOTICE:
This site contains copyrighted material the use of which has not always
been specifically authorized by the copyright owner. We are making
such material available in our efforts to advance understanding of
issues of significance. We believe this constitutes a ‘fair use’ of any
such copyrighted material as provided for in section 107 of the US
Copyright Law. In accordance with Title 17 U.S.C. Section 107, the
material on this site is distributed without profit to those who have
expressed a prior interest in receiving the included information for
research and educational purposes.
————————-
