Does
aspirin cause acute or chronic renal failure in
experimental animals and in humans?
D'Agati V.
Department of Pathology, College of Physicians
and Surgeons, Columbia University, 630 W 168th St,
New York, NY 10032 USA
American Journal of Kidney Diseases (USA), 1996,
28/1 Suppl. (S24-S29)
There are conflicting reports on the ability of
aspirin as a single agent to cause acute or
chronic renal failure in experimental animals.
Chronic administration of aspirin alone over 18 to
68 weeks in doses of 120 to 500 mg/kg/d has been
reported to cause renal papillary necrosis in
rate. However, some investigators have been unable
to produce renal papillary necrosis in other
species or in rats given lower divided doses
comparable to therapeutic doses used in humans. In
a variety of rat strains, aspirin administered as
a single high dose intravenously or by oral gavage
produces acute tubular necrosis of proximal
tubules, rarely accompanied by renal papillary
necrosis in susceptible strains. Several human
studies have addressed the chronic nephrotoxicity
of aspirin alone or relative risk of end-stage
renal disease in association with aspirin use
after correction for other analgesics. With the
exception of one case control study demonstrating
a low, but statistically significant risk of
end-stage renal disease in association with
aspirin use, all other case control studies and
several prospective studies have been unable to
identify a significant risk of chronic renal
failure in patients using aspirin alone in
therapeutic doses. In healthy adults, short-term
aspirin administration in therapeutic doses has no
effect on creatinine clearance, urine volume,
osmolar clearance, or sodium and potassium
excretion. However, in predisposed individuals
with glomerulonephritis, cirrhosis, and chronic
renal insufficiency, and in children with
congestive heart failure, short-term aspirin use
in therapeutic doses may precipitate reversible
acute renal failure. Acute aspirin intoxication
(>300 mg/kg) frequently causes acute renal
failure and doses of 500 mg/kg may be lethal.
Chronic salicylate intoxication has been reported
to cause reversible or irreversible acute renal
failure in association with a pseudosepsis
syndrome.
Elevated myocardial interstitial
norepinephrine concentration contributes to the
regulation of Na+,K+-ATPase in heart
failure
Lai L.-P.; Fan T.-H.M.; Delehanty J.M.; Yatani
A.; Liang C.-S.
Cardiology Unit, Department of Medicine, Univ. of
Rochester Medical Center, 601 Elmwood Avenue,
Rochester, NY 14642 USA
European Journal of Pharmacology (Netherlands),
1996, 309/3 (235-241)
Myocardial Na+,K+-ATPase is reduced in
congestive heart failure. To study the regulation
of Na+,K+-ATPase in congestive heart failure, we
performed Western and Northern blot analyses of
ventricular myocardium of dogs with pacing-induced
congestive heart failure and chronic
norepinephrine infusion, using isoform-specific
antibodies and cDNA probes. Congestive heart
failure and norepinephrine infusion caused similar
increases in myocardial interstitial
norepinephrine concentration and reductions of
myocardial Na+,K+-ATPase alpha3-subunit protein,
but differed in their effects on myocardial
Na+,K+-ATPase alpha3-subunit gene expression.
Chronic norepinephrine infusion produced no
changes in the steady-state mRNA level for the
alpha3-subunit of Na+,K+-ATPase, suggesting that
the changes in Na+,K+-ATPase protein were induced
via a post-transcriptional mechanism. In contrast,
down-regulation of the Na+,K+-ATPase
alpha3-subunit in the failing heart was
accompanied by a decreased alpha3-subunit mRNA
level, indicating the presence of a
transcriptional event. The alpha3-subunit protein
content and mRNA level were not affected by either
norepinephrine infusion or rapid ventricular
pacing. We conclude that, while elevated
myocardiaI interstitial norepinephrine levels may
contribute substantially to the down-regulation of
the Na+,K+-ATPase alpha3-subunit in the failing
myocardium, additional regulatory factors are
responsible for the decreased myocardial
alpha3-subunit mRNA expression in congestive heart
failure.
[Magnesium: current studies--critical
evaluation--consequences]
Meinertz T
Abteilung fur Kardiologie,
Universitatskrankenhaus Eppendorf, Hamburg.
Z Kardiol (Germany) 1996, 85 Suppl 6 p147-51
The therapeutic efficacy of magnesium has been
studied during recent years in a number of
cardiovascular diseases: supraventricular and
ventricular arrhythmias (multifocal atrial
tachycardia, Torsade de pointes-tachycardia,
glycoside-associated arrhythmias, sustained
ventricular tachycardia), acute myocardial
infarction, heart failure and arterial
hypertension. Although only a few of these
arrhythmias were studied under controlled
conditions, the therapeutic efficacy of
intravenous magnesium given in a high dose in
these arrhythmias seems to be established. By
contrary, the efficacy of magnesium in acute
myocardial infarction, congestive heart failure
and arterial hypertension remains controversial up
to now. Magnesium cannot be regarded as standard
therapy for example for patients with acute
myocardial infarction. (13 Refs.)
Nonsustained polymorphous ventricular
tachycardia during amiodarone therapy for atrial
fibrillation complicating cardiomyopathy.
Management with intravenous magnesium
sulfate.
Winters SL; Sachs RG; Curwin JH
Morristown Memorial Hospital, NJ 07962-1956,
USA.
Chest (United States) May 1997, 111 (5)
p1454-7
A case is presented in which amiodarone was
administered to suppress paroxysmal atrial
fibrillation in a patient with an idiopathic
cardiomyopathy. Eleven days after initiation of
therapy with amiodarone, the patient experienced
syncope and was noted to have recurrent episodes
of polymorphous ventricular tachycardia. The
patient was hospitalized and treated with a bolus
as well as continuous infusion of intravenous
magnesium sulfate. When the infusion was
transiently discontinued, recurrences of
polymorphous ventricular tachycardia were noted.
The probable proarrhythmic action of amiodarone,
although rare, is reviewed along with a discussion
of the novel use of intravenous magnesium sulfate
therapy. (6 Refs.)
Magnesium deficiency-related changes
in lipid peroxidation and collagen metabolism in
vivo in rat heart
Kumar BP; Shivakumar K; Kartha CC
Division of Cellular and Molecular Cardiology,
Sree Chitra Tirunal Institute for Medical Sciences
and Technology, Trivandrum, India.
Int J Biochem Cell Biol (England) Jan 1997, 29
(1) p129-34
Magnesium deficiency is known to produce a
cardiomyopathy, characterised by myocardial
necrosis and fibrosis. As part of the ongoing
investigations in this laboratory to establish the
biochemical correlates of these histological
changes, the present study probed the extent of
lipid peroxidation and alterations in collagen
metabolism in the heart in rats fed a
magnesium-deficient diet for 28, 60 or 80 days.
While lipid peroxidation was measured by the
thiobarbituric acid reaction, collagen turnover
rates and fibroblast proliferation were assessed
using [3H]-proline and [3H]-thymidine,
respectively. Tissue levels of magnesium and
calcium were determined by atomic absorption
spectrophotometry. A 39% increase in the cardiac
tissue level of thiobarbituric acid reactive
substances was observed on day 60 of deficiency (p
< 0.001). A marked drop in collagen deposition
rate (59%, p < 0.001%) on day 28 but a
significant rise in fractional synthesis rate
(12%, p < 0.001) and collagen deposition rate
(24%, p < 0.001) on day 60 were observed. A
fibroproliferative response in the heart was
evident on day 80 but not at earlier time-points.
Thus, the present study provides evidence of
increased lipid peroxidation and net deposition of
collagen in the myocardium in response to dietary
deficiency of magnesium. These changes were,
however, not directly related to alterations in
the tissue levels of Mg. It is suggested that the
increase in cardiac collagen synthesis and
fibroplasia associated with Mg deficiency may
represent reparative fibrogenesis, upon oxidative
damage to the cardiac muscle, and is mediated by a
mechanism independent of changes in cardiac tissue
levels of Mg.
[Value
of magnesium in acute myocardial infarct]
Beuckelmann DJ
Klinik III fur Innere Medizin, Universitat zu
Koln.
Z Kardiol (Germany) 1996, 85 Suppl 6 p129-34
Experiments in animal models of myocardial
infarction have provided evidence that early
magnesium infusion can limit the infarct size. One
mechanism that has been postulated to be of
importance is a protection of the cardiomyocyte
against a calcium overload during or after
ischemia. We had shown that in isolated human
myocytes from patient with ischemic cardiomyopathy
an increase of the extracellular magnesium
concentration could block the L-type-calcium
current in a dose dependent manner. Until recently
only small, uncontrolled studies have indicated
there may be a reduction of mortality due to
myocardial infarction when intravenous magnesium
infusion was added to standard therapy. However,
two recently published randomized studies showed
different results, although similar doses of
magnesium were used (70-80 mmol magnesium over 24
h). The LIMIT-2-study was a double-blind, placebo
controlled investigation of over 2300 patients
with suspected myocardial infarction. Magnesium
infusion was associated with a reduction of the 28
day mortality by 24%. The ISIS-4-study on over
50,000 patients with suspected myocardial
infarction did not show any positive effect of
magnesium on mortality. Major differences between
both studies were differences in thrombolysis
(LIMIT-2:1/3, ISIS-4: 70%). Furthermore, in
LIMIT-2 magnesium infusion was started as early as
possible, whereas in ISIS-4 magnesium was given
after the end of thrombolytic therapy. In can be
concluded that magnesium therapy in acute
myocardial infarction after thrombolytic therapy
is not useful. However, in patients where
thrombolytic therapy is not feasable, early
infusion of magnesium may be beneficial. As side
effects are minor and costs are low, a therapeutic
trial may be warranted, although a final decision
on the effects of magnesium cannot be made. (15
Refs.)
NADH-coenzyme Q reductase (complex I)
deficiency: heterogeneity in phenotype and
biochemical findings.
Pitkanen S; Feigenbaum A; Laframboise R;
Robinson BH
Department of Pediatrics, University of Toronto,
Ontario, Canada.
J Inherit Metab Dis (Netherlands) 1996, 19 (5)
p675-86
Twelve patient cell lines with biochemically
proven complex I deficiency were compared for
clinical presentation and outcome, together with
their sensitivity to galactose and menadione
toxicity. Each patient had elevated lactate to
pyruvate ratios demonstrable in fibroblast
cultures. Each patient also had decreased
rotenone-sensitive NADH-cytochrome c reductase
(complexes I and III) with normal succinate
cytochrome c reductase (complexes II and III) and
cytochrome oxidase (complex IV) activity in
cultured skin fibroblasts, indicating a deficient
NADH-coenzyme Q reductase (complex I) activity.
The patients fell into five categories: severe
neonatal lactic acidosis; Leigh disease;
cardiomyopathy and cataracts; hepatopathy and
tubulopathy; and mild symptoms with lactic
acidaemia. Cell lines from 4 out of the 12
patients were susceptible to both galactose and
menadione toxicity and 3 of these also displayed
low levels of ATP synthesis in
digitonin-permeabilized skin fibroblasts from a
number of substrates. This study highlights the
heterogeneity of complex I deficiency at the
clinical and biochemical level.
Familial cardiomyopathy with
cataracts and lactic acidosis: a defect in complex
I (NADH-dehydrogenase) of the mitochondria
respiratory chain.
Pitkanen S; Merante F; McLeod DR; Applegarth D;
Tong T; Robinson BH
Department of Pediatrics, University of Toronto,
Quebec, Canada.
Pediatr Res (United States) Mar 1996, 39 (3)
p513-21
Four patients in one generation of a multiply
consanguineous pedigree died with cardiomyopathy,
cataracts, and lactic acidemia. Postmortem heart
and skeletal muscle tissues from one patient were
analyzed. A low (12% control) activity of NADH-CoQ
reductase (complex I) in heart and normal activity
in skeletal muscle mitochondria was found.
Cultured skin fibroblasts obtained from two
individuals in the pedigree showed elevated
lactate to pyruvate ratios in the range of 2 to
3.5 times normal and decreased complex I + III
activity (42 and 54% of control activities) in
isolated mitochondria. Western blot analysis and
enzymatic assay showed normal levels of
CuZn-superoxide dismutase, but grossly elevated
levels of the mitochondrial Mn-superoxide
dismutase. Southern blot analysis in heart muscle
cells from the patient tested revealed multiple
mitochondrial DNA deletions which indicate free
oxygen radical damage. We hypothesize that a
nuclear-encoded defect in the respiratory chain is
responsible for excessive free oxygen radical
production in these infants which contributes to
the prenatal onset of cardiomyopathy and
cataracts.
Comparison of calcium-current in
isolated atrial myocytes from failing and
nonfailing human hearts.
Cheng TH; Lee FY; Wei J; Lin CI
Graduate Institute of Life Sciences, National
Defense Medical Center, Taipei, Taiwan, Republic
of China.
Mol Cell Biochem (Netherlands) Apr 12-26 1996,
157 (1-2) p157-62
To identify possible alterations of the L-type
calcium currents (I(Ca),L) in cardiomyopathy,
I(Ca),L were recorded in atrial myocytes
dissociated from the nonfailing heart (NF) of
patients undergoing corrective open-heart surgery
and explanted failing heart (FH) of patients with
dilated cardiomyopathy undergoing heart
transplantation. The patch-clamp technique was
applied in the single-electrode whole-cell mode.
The electrophysiological properties of I(Ca),L,
including cell capacitance and current density,
were similar in atrial myocytes from both groups
of patients. Further to identify possible
alterations of the myocardial beta-adrenergic
pathway in cardiomyopathy, we examined the effects
of isoproterenol,forskolin, 8-Br-cAMP and
IBMX on I(Ca),L in both groups of atrial myocytes.
Perfusion of isoproterenol (1 microM)
significantly increased the peak I(Ca),L by 515
+/- 44% in 6 atrial myocytes from NF but increased
only by 135 +/- 25% in 27 atrial myocytes from FH.
However, forskolin (1 microM) or 8-Br-cAMP (0.1
mM) increased the peak I(Ca),L to a similar extent
in atrial myocytes from NF and FH. IBMX (20
microM) also induced a comparable increase in the
peak I(Ca),L by 213 +/- 31% (n = 5) and 207 +/-
59% (n = 4) in atrial myocytes from NF and FH,
respectively. The above findings suggest that in
atrial myocytes obtained from FH the
beta-adrenoceptor numbers might be decreased but
no impairment of the signal transduction cascade
occurred beyond the GTP binding proteins
level.
Mitochondrial complex I deficiency
leads to increased production of superoxide
radicals and induction of superoxide
dismutase.
Pitkanen S; Robinson BH
Department of Pediatrics, University of Toronto,
Ontario, Canada.
J Clin Invest (United States) Jul 15 1996, 98 (2)
p345-51
Mitochondria were isolated from skin fibroblast
cultures derived from healthy individuals
(controls) and from a group patients with complex
I (NADH-CoQ reductase) deficiency of the
mitochondrial respiratory chain. The complex I
deficient patients included those with fatal
infantile lactic acidosis (FILA), cardiomyopathy
with cataracts (CC), hepatopathy with tubulopathy
(HT), Leigh's disease (LD), cataracts and
developmental delay (CD), and lactic acidemia in
the neonatal period followed by mild symptoms
(MS). Production of superoxide radicals, on
addition of NADH, were measured using the
luminometric probe lucigenin with isolated
fibroblast mitochondrial membranes. Superoxide
production rates were highest with CD and
decreased in the order CD >> MS > LD >
control > HT > FILA = CC. The quantity of
Mn-superoxide dismutase (MnSOD), as measured by
ELISA techniques, however, was highest in CC and
FILA and lowest in CD. Plots of MnSOD quantity
versus superoxide production showed an inverse
relationship for most conditions with complex I
deficiency. We hypothesize that oxygen radical
production is increased when complex I activity is
compromised. However, the observed superoxide
production rates are modulated by the variant
induction of MnSOD which decreases the rates,
sometimes below those seen in control fibroblast
mitochondria. In turn, we show that the variant
induction of MnSOD is most likely a function of
the change in the redox state of the cell
experienced rather than a result of the complex I
defect per se.
A
preliminary study of growth hormone in the
treatment of dilated cardiomyopathy
Fazio S; Sabatini D; Capaldo B; Vigorito C;
Giordano A; Guida R; Pardo F; Biondi B; Sacca L
Department of Internal Medicine, University
Federico II, Naples, Italy.
N Engl J Med (United States) Mar 28 1996, 334
(13) p809-14
Comment in N Engl J Med 1996 Mar
28;334(13):856-7
Comment in: N Engl J Med 1996 Aug 29;335(9):672;
discussion 673-4
BACKGROUND. Cardiac hypertrophy is a
physiologic response that allows the heart to
adapt to an excess hemodynamic load. We
hypothesized that inducing cardiac hypertrophy
with recombinant human growth hormone might be an
effective approach to the treatment of idiopathic
dilated cardiomyopathy, a condition in which
compensatory cardiac hypertrophy is believed to be
deficient.
METHODS. Seven patients with idiopathic dilated
cardiomyopathy and moderate-to-severe heart
failure were studied at base line, after three
months of therapy with human growth hormone, and
three months after the discontinuation of growth
hormone. Standard therapy for heart failure was
continued throughout the study. Cardiac function
was evaluated with Doppler echocardiography,
right-heart catheterization, and exercise
testing.
RESULTS. When administered at a dose of 14 IU
per week, growth hormone doubled the serum
concentrations of insulin-like growth factor I.
Growth hormone increased left-ventricular-wall
thickness and reduced chamber size significantly.
Consequently, end-systolic wall stress (a function
of both wall thickness and chamber size) fell
markedly (from a mean [+/-SE] of 144+/-11 to
85+/-8 dyn per square centimeter, P<0.001).
Growth hormone improved cardiac output,
particularly during exercise (from 7.4+/-0.7 to
9.7+/-0.9 liters per minute, P=0.003), and
enhanced ventricular work, despite reductions in
myocardial oxygen consumption (from 56+/-6 to
39+/-5 ml per minute, P=0.005) and energy
production (from 1014+/-100 to 701+/-80 J per
minute, P=0.002). Thus, ventricular mechanical
efficiency rose from 9+/-2 to 21+/-5 percent
(P=0.006). Growth hormone also improved clinical
symptoms, exercise capacity, and the patients'
quality of life. The changes in cardiac size and
shape, systolic function, and exercise tolerance
were partially reversed three months after growth
hormone was discontinued.
CONCLUSIONS. Recombinant human growth hormone
administered for three months to patients with
idiopathic dilated cardiomyopathy increased
myocardial mass and reduced the size of the left
ventricular chamber, resulting in improvement in
hemodynamics, myocardial energy metabolism, and
clinical status.
Effect
of protection and repair of injury of
mitochondrial membrane-phospholipid on prognosis
in patients with dilated
cardiomyopathy
Ma A, Zhang W, Liu Z
Department of Cardiology, First Affiliated
Hospital of Xi'an Medical University, China.
Blood Press Suppl. 1996;3:53-5
We have already proved that the mitochondrial
membrane-phospholipid (MMP) injury changes of
peripheral lymphocytes in patients with heart
failure can be used as an injury indicator of
myocardia, and are related to the long-term
prognosis. In the present study, MMP localization
of the peripheral lymphocytes was performed by
modified Demer's tricomplex flocculation method,
and we compared the changes, after classification,
between the pre-treatment and the 12-week
post-treatment, of coenzyme Q10 (Co.Q10) and
captopril in 61 hospitalized patients with dilated
cardiomyopathy (DCM). They were followed up for
16.1 +/- 7.8 months (mean). The results showed
that compared with the placebo, Co.Q10 and
captopril could significantly protect against and
repair MMP injury and improve the heart function
of patients with DCM after 12 weeks, and the
2-year survival rate rose significantly by 72.7%
for Co.Q10, and 64.0% for captopril, vs 24.7% for
placebo. As for Longrank test, X2 equals 4.660 and
6.318, respectively, with both p < 0.05. The
aforementioned results indicate that MMP injury of
peripheral lymphocytes can predict the prognosis
of the patients with DCM, thus the protection and
repairment of MMP injury can improve the
life-quality and prolong the life-span of the
patients.
[Therapeutic effects of coenzyme Q10
on dilated cardiomyopathy: assessment by
123I-BMIPP myocardial single photon emission
computed tomography (SPECT): a multicenter trial
in Osaka University Medical School
Group]
Nishimura T; Hori M
Tracer Kinetics and Nuclear Medicine, Osaka
University, Japan.
Kaku Igaku (Japan) Jan 1996, 33 (1) p27-32
To evaluate therapeutic effects of Cenzyme Q10
(CoQ10), 15 patients with dilated cardiomyopathy
were investigated by 123I-BMIPP myocardial single
photon emission computed tomography (SPECT). The
BMIPP defect score was determined
semiquantitatively by using representative short
and long axial SPECT images. Mean BMIPP defect
score with CoQ10 treatment was significantly low,
7.7 +/- 6.1 compared to 12.7 +/- 7.4 without CoQ10
treatment. On the other hand, in 8 patients of
dilated cardiomyopathy, % fractional shortening
using echocardiography was not different before
and after CoQ10 treatment. In conclusion,
123I-BMIPP myocardial SPECT was proved to be
sensitive to evaluate the therapeutic effects of
CoQ10, which improve myocardial mitochondrial
function, in the cases of dilated
cardiomyopathy.
The
effects of calcium channel blockers on blood
fluidity.
Koenig W, Ernst E
Department of Medicine (Cardiology), Klinikum der
Universitat, Ulm, F.R.G.
J Cardiovasc Pharmacol 1990;16 Suppl 6:S40-4
Although vasodilation, direct cardiac actions,
or both represent the main properties of calcium
channel blockers, there are further pharmacologic
effects that may be therapeutically relevant. For
example, hemorrheological effects, which have been
demonstrated for a variety of calcium antagonists,
have received relatively little attention to date.
Hemorrheology describes the mechanics of blood and
its components. It is of particular interest in
the context of cardiovascular disease, as it has
been shown that under certain conditions (reduced
pump function, impaired vasomotor reserve),
parameters of blood fluidity may be crucial for
tissue perfusion. Whole-blood viscosity is the
dominating factor in large arteries. For
geometrical reasons, plasma viscosity and the
rheological properties of blood cells may become
of paramount importance at the microcirculatory
level. In ischemic states, erythrocytes may be
depleted of ATP, which they need for maintenance
of normal shape and for transformation. This
results in rigidification of the red blood cell
and hindrance of its passage in the
microcirculatory bed. Hence, blood flow
deteriorates with the consequence of further
unfavorable changes of the "milieu interieur,"
leading to the induction of a vicious cycle.
Although effects on several hemorrheological
parameters, for example, whole-blood viscosity,
plasma viscosity, and red cell aggregation, can be
demonstrated for various calcium channel blockers,
the main rheological effects of these compounds
are believed to consist in the improvement of
erythrocyte deformability. When the ATP-dependent
calcium pump is impaired in ischemia, calcium
channel blockers may inhibit the slow inward
transmembrane calcium flux and prevent the
accumulation of intracellular calcium. (33
Refs.)
Increased whole blood and plasma
viscosity in patients with angina pectoris and
'normal' coronary arteries
Larsson H, Gustavsson CG, Odeberg H, Persson
S
Department of Internal Medicine, University
Hospital, Lund, Sweden.
Acta Med Scand 1988;224(2):109-14
Blood and plasma viscosity was measured in
eight patients with typical effort-induced angina
pectoris who did not have coronary artery stenosis
at angiography. The same variables were studied in
14 patients with angina pectoris and verified
coronary artery desease that in most cases was
extensive. Both groups of patients had
significantly higher viscosity values in whole
blood, at natural hematocrit as well as at
standardized hematocrit (45%), than 25 healthy
subjects serving as a reference group. Plasma
viscosity was also significantly elevated in both
patient groups. The patients without coronary
artery stenosis had as high blood and plasma
viscosity values as had the stenosis group. It is
concluded that increased blood and plasma
viscosity should be added to the list of
pathological findings in patients with angina
pectoris in the absence of organic coronary artery
stenosis.
Can
lifestyle changes reverse coronary heart
disease?
Ornish D, Brown SE, Scherwitz LW, Billings JH,
Armstrong WT, Ports TA, McLanahan SM, Kirkeeide
RL, Brand RJ, Gould KL
Pacific Presbyterian Medical Center, Sausalito,
California.
Lancet 1990 Jul 21;336(8708):129-33
In a prospective, randomised, controed trial to
determine whether comprehensive lifestyle changes
affect coronary atherosclerosis after 1 year, 28
patients were assigned to an experimental group
(low-fat vegetarian diet, stopping smoking, stress
management training, and moderate exercise) and 20
to a usual-care control groups. 195 coronary
artery lesions were analysed by quantitative
coronary angiography. The average percentage
diameter stenosis regressed from 40.0 (SD 16.9)%
to 37.8 (16.5)% in the experimental group yet
progressed from 42.7 (15.5)% to 46.1 (18.5)% in
the control group. When only lesions greater than
50% stenosed were analysed, the average percentage
diameter stenosis regressed from 61.1 (8.8)% to
55.8 (11.0)% in the experimental group and
progressed from 61.7 (9.5)% to 64.4 (16.3)% in the
control group. Overall, 82% of experimental-group
patients had an average change towards regression.
Comprehensive lifestyle changes may be able to
bring about regression of even severe coronary
atherosclerosis after only 1 year, without use of
lipid-lowering drugs.
The
natural history of atherosclerosis: An ecologic
perspective
Mozar HN, Bal DG, Farag SA
Chronic Diseases Control Branch, California State
Department of Health Services, Sacramento
94234-7320.
Atherosclerosis 1990 May;82(1-2):157-64
Virologic findings reported in recent
atherosclerosis literature may have profound
implications. To assess them, we have viewed
atherosclerosis in a broad biologic context and
against a background of environmental, behavioral,
and social change. Reasonable grounds exist, we
believe, for regarding atherosclerosis as a
chronic, low-grade infectious macroangiopathy
which is aggravated by hypercholesterolemia and
other recognized risk factors. There are probably
multiple infective pathogens and transmission
routes. The putative agents that initiate
atherosclerosis might include ubiquitous viruses
that produce clinically unapparent infections in
many animal species. Pathways for their
transmission to humans may include the food chain
and contaminated water. Food-chain transmission
may have been largely responsible for the parallel
increases of meat consumption and mortality from
coronary heart disease in the United States during
the middle third of the century. It proring
thermal intervention as a heretofore unrecognized
factor that may actually best account for the
surprising reversal of climbing heart disease
mortality rates. Improved sanitation and food
hygiene as well as improvements in diet,
lifestyle, and medical care may have shaped the
downward mortality curve. The virus hypothesis may
reconcile apparent epidemiologic conflicts and
elucidate the natural history of
atherosclerosis.
Concordant dyslipidemia, hypertension
and early coronary disease in Utah
families
Williams RR, Hunt SC, Wu LL, Hopkins PN,
Hasstedt SJ, Schumacher MC, Stults BM, Kuida H
Department of Medicine, University of Utah, Salt
Lake City.
Klin Wochenschr 1990;68 Suppl 20:53-9
A detailed family history questionnaire
collected from families of 35,000 sixteen year old
high school students in Utah was used to identify
population-based sibships with two or more living
adults affected with hypertension under age 60 or
coronary artery disease before age 55. Detailed
clinical and biochemical evaluations performed
during a four-hour visit to a research clinic
provided data to test for concordant abnormalities
in siblings with either early hypertension or
early coronary heart disease. A new syndrome,
familial dyslipidemic hypertension (FDH), was
found in 48% of the hypertensive sibships. In
these FDH subjects, 68% had HDL-cholesterol below
the 10th percentile, 49% had triglyceride level
above the 90th percentile, and 27% had LDL levels
above the 90th percentile. When compared to
normolipidemic hypertensive subjects, persons with
FDH had significantly elevated fasting plasma
insulin levels, increased subscapular skinfold
thickness, increased knee width and wrist
circumference, and increased levels of VLDL
cholesterol and apolipoprotein B. In coronary
sibships, concordant abnormalities for lipids were
consistent with familial combined hyperlipidemia
in 30-40% of sibships, FDH in 15-45% of sibships,
and low HDL-C (with normal cholesterol) in 10%.
Concordant normal lipids were found in only 15% of
sibships. These data suggest that inherited
metabolic abnormalities likely explain some
co-aggregation of hyperinsulinemia, obesity,
hypertension, and early coronary heart disease.
Current knowledge also suggests these metabolic
abnormalities could be treated or prevented with
appropriate modification in lifestyle factors such
as diet and exercise as well as through the use of
prescription medications.
Mediterranean alpha-linolenic
acid-rich diet in secondary prevention of coronary
heart disease.
de Lorgeril M, Renaud S, Mamelle N, Salen P,
Martin JL, Monjaud I, Guidollet J, Touboul P,
Delaye J
INSERM (Institut National de la Sante et de la
Recherche Medicale), Units 63, Bron, France.
Lancet 1994 Jun 11;343(8911):1454-9
Published erratum appears in Lancet 1995 Mar
18;345(8951):738
In a prospective, randomised single-blinded
secondary prevention trial we compared the effect
of a Mediterranean alpha-linolenic acid-rich diet
to the usual post-infarct prudent diet. After a
first myocardial infarction, patients were
randomly assigned to the experimental (n = 302) or
control group (n = 303). Patients were seen again
8 weeks after randomisation, and each year for 5
years. The experimental group consumed
significantly less lipids, saturated fat,
cholesterol, and linoleic acid but more oleic and
alpha-linolenic acids confirmed by measurements in
plasma. Serum lipids, blood pressure, and body
mass index remained similar in the 2 groups. In
the experimental group, plasma levels of albumin,
vitamin E, and vitamin C were increased, and
granulocyte count decreased. After a mean follow
up of 27 months, there were 16 cardiac deaths in
the control and 3 in the experimental group; 17
non-fatal myocardial infarction in the control and
5 in the experimental groups: a risk ratio for
these two main endpoints combined of 0.27 (95% CI
0.12-0.59, p = 0.001) after adjustment for
prognostic variables. Overall mortality was 20 in
the control, 8 in the experimental group, an
adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p =
0.02). An alpha-linolenic acid-rich Mediterranean
diet seems to be more efficient than presently
used diets in the secondary prevention of coronary
events and death.
Effect
of antioxidant-rich foods on plasma ascorbic acid,
cardiac enzyme, and lipid peroxide levels in
patients hospitalized with acute myocardial
infarction
Singh RB; Niaz MA; Agarwal P; Begom R; Rastogi
SS
Heart Research Laboratory, Medical Hospital,
Moradabad, UP, India.
J Am Diet Assoc 1995 Jul;95(7):775-80
Objective: To determine whether a fat- and
energy-reduced diet rich in antioxidant vitamins C
and E, beta carotene, and soluble dietary fiber
reduces free-radical stress and cardiac enzyme
level and increases plasma ascorbic acid level 1
week after acute myocardial infarction.
Design: Randomized, single blind, controlled
study.
Setting: Primary- and secondary- care research
center for patients with myocardial
infarction.
Subjects: All subjects with suspected acute
myocardial infarction (n=505) were considered for
entry to the study. Subjects with definite or
possible acute myocardial infarction and unstable
angina (according to World Health Organization
criteria) were assigned to either an intervention
diet (n=204) or a control diet (n=202) within 48
hours of symptoms of infarction. Interventions:
Intervention and control groups were advised to
consume a fat-reduced, oil- substituted diet. The
intervention group was also advised to cat more
fruits, vegetable soup, pulses, and crushed
almonds and walnuts mixed with skim milk.
Main outcome measures: Reduction in plasma
lipid peroxide and lactate dehydrogenase cardiac
enzyme levels, increase in plasma ascorbic acid
level, and compliance with diet, especially with
vitamin C intake as determined by chemical
analysis.
Statistical analysis: A two-sample t test using
one-way analysis of variance for comparison of
data.
Results: Plasma lipid peroxide level decreased
significantly in the intervention group compared
with the control group (0.59 pmol/L in the
intervention group and 0.10 pmol/L in the control
group; 95% confidence interval of difference=0.19
to 0.83). Lactate dehydrogenase level increased
less in the intervention group than in the control
group (427.7 vs 561.2 U/L; confidence interval of
difference=82.9 to 184.7). Plasma ascorbic acid
level increased more in the intervention group
than in the control group (23.38 vs 7.95
micromol/L; confidence interval of difference=
12.85 to 26.13). Applications/conclusions:
Consumption of an antioxidant-rich diet may reduce
the plasma levels of lipid peroxide and cardiac
enzymeioxidant- rich foods may reduce myocardial
necrosis and reperfusion injury induced by oxygen
free radicals.
Dietary
supplementation with orange and carrot juice in
cigarette smokers lowers oxidation products in
copper-oxidized low-density
lipoproteins
Abbey M, Noakes M, Nestel PJ
Division of Human Nutrition, Commonwealth
Scientific and Industrial Research Organization,
Adelaide, Australia.
J Am Diet Assoc 1995 Jun;95(6):671-5
Objective: Our objective was to evaluate the
effect of daily supplementation with foods high in
vitamin C and beta carotene on plasma vitamin
levels and oxidation of low-density lipoprotein
(LDL) in cigarette smokers.
Subjects: Fifteen normolipidemic male cigarette
smokers who did not usually take vitamin
supplements were recruited into the study.
Interventions: Throughout the study, subjects
consumed a diet rich in polyunsaturated fatty
acids, which provided 36% of energy as fat: 18%
from meat, dairy products, vegetable oils, and fat
spreads and 18% from walnuts (68 g/day). Subjects
consumed a vitamin-free drink daily for 3 weeks;
then for 3 weeks they consumed daily supplements
of orange juice (145 mg vitamin C) and carrot
juice (16 mg beta carotene).
Results: Vitamin-rich food supplements raised
plasma levels of ascorbic acid (1.6-fold;
P<.01) and beta carotene (2.6-fold; P<.01).
Malondialdehyde, one end product of oxidation, was
lower in copper-oxidized LDL after vitamin
supplementation (meanplus or minusstandard
error=65.7plus or minus2.0 and 57.5plus or
minus2.9 micromol/g LDL protein before and after
supplementation, respectively; P<.01). Rate of
LDL oxidation and lag time before the onset of LDL
oxidation were not affected by antioxidant
supplementation.
Conclusions: In habitual cigarette smokers,
antioxidant vitamins, which can be feasibly
provided from food, partly protected LDL from
oxidation despite a diet rich in polyunsaturated
fatty acids.
Women,
hormones and blood pressure
Khaw KT
Clinical Gerontology Unit, University of
Cambridge School of Medicine, Addenbrooke's
Hospital, UK.
Can J Cardiol 1996 Jun;12 Suppl D:9D-12D
Raised blood pressure is an important risk
factor for both coronary artery disease and stroke
in women. In terms of exogenous sex hormones, use
of premenopausal oral contraceptives has been
consistently associated with higher blood pressure
levels; both estrogenic and progestogenic
components have been implicated. In contrast, a
randomized trial has shown no effect of
postmenopausal hormone use on blood pressure.
Observational studies indicate a protective effect
of postmenopausal estrogen use on coronary artery
disease. This is probably largely mediated through
effects on lipoproteins and not blood pressure;
data on post menopausal estrogen use and stroke
risk are less consistent. Treatment trials have
demonstrated beneficial effects of lowering blood
pressure on cardiovascular disease, particularly
regarding stroke in women. The women most likely
to benefit from individually based clinical
preventive interventions for cardiovascular
disease, such as hypertension treatment or
estrogen replacement therapy, are women who have
high absolute risk of cardiovascular disease, ie,
older women with high risk factor levels with a
family or existing history of cardiovascular
disease. Nevertheless, the large international
variation in rates of cardiovascular disease
indicate the large potential for prevention and
suggest that most women are likely to benefit from
lifestyles conducive to cardiovascular health,
that is, increasing physical activity, not smoking
and following diets low in sodium and saturated
fat and high in fruits and vegetables.
Protective effect of fruits and
vegetables on development of stroke in
men
Gillman MW, Cupples LA, Gagnon D, Posner BM,
Ellison RC, Castelli WP, Wolf PA
Department of Ambulatory Care and Prevention,
Harvard Medical School, Boston, MA 02215, USA.
JAMA 1995 Apr 12;273(14):1113-7
Objective. - To examine the effect of fruit and
vegetable intake on risk of stroke among
middle-aged men over 20 years of follow-up.
Design. - Cohort.
Setting. - The Framingham Study, a
population-based longitudinal study.
Participants. - All 832 men, aged 45 through 65
years, who were free of cardiovascular disease at
baseline (1966 through 1969).
Measurements and Data Analysis. - The diet of
each subject was assessed at baseline by a single
24- hour recall. The estimated total number of
servings per day of fruits and vegetables was the
exposure variable for this analysis. Using
Kaplan-Meier survival analysis, we examined
age-adjusted cumulative incidence of stroke by
quintile of servings per day. To adjust for
multiple covariates, we used proportional hazards
regression to calculate the relative risk (RR) of
stroke for each increment of throe servings per
day.
Main Outcome Measure. - Incidence of completed
strokes and transient ischemic attacks.
Results. - At baseline, the mean (plus or
minusSD) number of fruit and vegetable servings
per day was 5.1 (plus or minus2.8). During
follow-up there were 97 incident strokes,
including 73 completed strokes and 24 transient
ischemic attacks. Age-adjusted risk of stroke
decreased across increasing quintile of servings
per day (log rank P for trend, .01). Age-adjusted
RR for all stroke, including transient ischemic
attack, was 0.78 (95% confidence interval (CI),
0.62 to 0.98) for each increase of three servings
per day. For completed stroke the RR was 0.74 (95%
CI, 0.57 to 0.96); for completed stroke of
ischemic origin the RR was 0.76 (95% CI, 0.57 to
1.02); and for completed stroke of hemorrhagic
origin, 0.49 (95% CI, 0.25 to 0.95). Adjustment
for body mass index, cigarette smoking, glucose
intolerance, physical activity, blood
pressurerially change the results.
Conclusion. - Intake of fruits and vegetables
may protect against development of stroke in
men.
The
effect of caffeine on ventricular ectopic activity
in patients with malignant ventricular
arrhythmia
Graboys TB, Blatt CM, Lown B
Cardiovascular Division, Brigham and Women's
Hospital, Harvard Medical School, Boston, MA.
Arch Intern Med 1989 Mar;149(3):637-9
We evaluated the effect of caffeine on
ventricular ectopic activity in a group of 50
consecutive patients with malignant ventricular
arrhythmia. The clinical arrhythmia in these
patients (mean age, 61 years) was recurrent
ventricular tachycardia in 21 (42%), ventricular
fibrillation in three (6%), and symptomatic
nonsustained ventricular tachycardia in 26 (52%).
Forty-two (84%) had either ischemic heart disease
or cardiomyopathy. Each patient underwent two
short-term drug trials on successive days,
receiving either decaffeinated coffee mixed with
200 mg of caffeine or the decaffeinated drink
alone. Continuous electrocardiographic recordings
were made during the 30-minute control period, the
three-hour observation period, and the hourly
bicycle exercise tests. Forty-five patients (90%)
exhibited ventricular couplets and 29 patients
(58%) had salvos of ventricular tachycardia during
the testing. However, no differences between the
caffeine and decaffeinated trials were observed in
either individual or group data on total or
repetitive ventricular arrhythmia. Serum
catecholamine levels reflected the average
increase in serum caffeine level but were not
associated with enhanced arrhythmia. We found no
evidence that a modest dose of caffeine is
arrhythmogenic, even among patients with known
life-threatening arrhythmia.
Coffee,
cocktails and coronary candidates
Kannel WB
N Engl J Med 1977 Aug 25;297(8):443-4
In this issue of this journal, Yano et al.
publish that they found no even be beneficial.e in
moderation is harmful, and they report that
Pharmacologic effects of caffeine and other
unspecified ingredients of coffee have been cited
to explain an alleged relation to myocardial
infarction. In contrast to some retrospective
studies, all prospective studies have failed to
implicate coffee as an independent contributor to
death from coronary heart disease or myocardial
infarction. The report of the Boston Collaborative
Drug Surveillance program provoked much
speculation regarding whether coffee consumption
raises the risk of myocardial infarction. Neither
the press nor the health professionals heeded the
authors' caution that the possible role of coffee
drinking in acute myocardial infarction requires
'reevaluation'. The authors referred briefly to
possible selective biases in retrospective
studies, but neither they nor their readers
apparently paid sufficient heed. As regards the
use of ethanol, modern methods of evaluation have
not substantiated the old concept of a beneficial
effect on coronary blood flow. The hazard of
alcohol in cardiac disease has long been
attributed to coexisting malnutrition. Recent
evidence supports a cardiotoxic role for alcohol
taken in large amounts; there is ample evidence
that alcohol abuse can cause cardiomyopathy, and
it has been associated with dysrhythmias and
deterioration of left ventricular performance.
However, the data linking alcohol to coronary
morbidity and mortality have been inexplicably
inconsistent. But, although heavy use of alcohol
is clearly toxic to the heart muscle, this fact
does not preclude a beneficial effect of moderate
use on the coronary vessels. Lipid abnormalities,
particularly hypertriglyceridemia, have been
documented in response to an alcohol challenge,
but these abnormalities are transient and appear
to have no lasting ill effects. For the present,
one can state that physicians, in protecting
patients against atherosclerotic cardiovascular
disease, have no good reason to restrict social
drinking in moderation. Although one does not want
to make too much of the apparent benefits, what
data there are show, if anything, a lower
incidence in those who drink a little. There is
also insufficient evidence to support the
restriction of coffee drinking. For patients who
have an irritable myocardium subject to
dysrhythmia, restriction of coffee and alcohol
seems indicated.
Concentrations of magnesium, calcium,
potassium, and sodium in human heart muscle after
acute myocardial infarction.
Speich M; Bousquet B; Nicolas G
Clin Chem 1980 Nov;26(12):1662-5
Atomic absorption spectrometry was used to
measure magnesium, calcium, and sodium, and
emission spectrometry to measure potassium, in
myocardium (left and right ventricles) of 26
control subjects who died of acute trauma. Results
were expressed in mumol/g of proteins. Mg/Ca and
K/Na ratios were also determined. The same
measurements were made in 24 patients who died
from acute myocardial infarction. Samples were
also taken from the necrotic area. Mg/Ca and K/Na
ratios were significantly higher in the left
ventricle of both populations, thus providing
evidence of anatomical and physiological
differences between the two ventricles. As a
result of cytolysis and anoxia, the Mg/Ca ratio
was very significantly inverted, and the K/Na
ratio very significantly smaller, In these
clinical conditions arrhythmias could certainly be
considered likely, and there is reason to believe
that magnesium depletion may be a cause of
arrhythmias.
[Therapeutic efficacy of pantothenic
acid preparations in ischemic heart disease
patients]
Borets VM, Lis MA, Pyrochkin VM, Kishkovich VP,
Butkevich ND
Vopr Pitan 1987 Mar-Apr;(2):15-7
The therapeutic effectiveness of the
pantothenic acid drugs: calciipantothenas and
pantethine, was studied in 182 patients with
coronary heart disease and stable angina of
effort. It is shown that both the drugs produce
favourable effects on certain parameters of
hemodynamics, on the metabolism of lipids,
riboflavin and ascorbic acid. It is recommended
that the administration of calciipantothenas in a
dose of 300 mg/day, during 3 weeks, be included
into the combined treatment of coronary patients
with no manifest disorders of lipid metabolism.
Patients with manifest hyperlipidemia should be
administered pantethine in a dose of 500
mg/day.
Antifibrillatory effect of
tetrahydroberberine.
Sun AY, Li DX
Department of Pharmacology, Nanjing Medical
College, China.
Chung Kuo Yao Li Hsueh Pao 1993
Jul;14(4):301-5
Electric stimulation and drug-induced
ventricular fibrillation (VF), monophasic action
potentials (MAPhydroberberine (THB) in rabbits,
rats or guinea pigs. At doses of 5, 10, and 20
mg.kg-1, i.v. THB increased the ventricular
fibrillation threshold, and the BaCl2-induced VF
was also prevented or terminated by THB in
rabbits. Centrogenic VF induced by icv aconitine
in rats was inhibited by pretreatment with THB in
a dose-dependent manner, whereas VF induced by iv
ouabain in guinea pig was inhibited to a lesser
degree. For MAP, the duration at 90%
repolarization (MAPD90) was prolonged remarkably,
whereas the MAPD20, the MAP amplitude, and the
maximal velocity of phase 0 were shortened or
decreased slightly. The amplitudes of early
afterdepolarization produced by cesium chloride
(CsCl) were attenuated, while the cumulative
threshold doses of CsCl for sustained ventricular
tachycardia were elevated by THB. These results
indicated that THB had an potent antifibrillatory
effect, which might be attributed to its blockade
of potassium, calcium, and sodium currents.
Effects
of tetrahydroberberine on ischemic and reperfused
myocardium in rats.
Zhou J, Xuan B, Li DX
Department of Pharmacology, Nanjing Medical
College, China.
Chung Kuo Yao Li Hsueh Pao 1993
Mar;14(2):130-3
The effects of tetrahydroberberine (THB) on
ischemic and reperfused myocardium were studied in
comparison with verapamil (Ver). In anesthetized
rats, THB and its analogues, l-THP and l-SPD,
reduced the infarct size after 4 h of left
anterior descending coronary artery (LAD)
ligation. In Langendorff hearts, in common with
Ver, THB 1 and 10 mumol.L-1 markedly decreased the
incidences of ventricular tachycardia (VT) and
ventricular fibrillation (VF) in the reperfusion
period. The malondialdehyde content and xanthine
oxidase activity were also decreased in global
ischemic-reperfused hearts pretreated with THB (P
< 0.01, or P < 0.05). It suggested that THB
could protect the myocardium from ischemic and
reperfusion injury.
[Ventricular tachyarrhythmias treated
with berberine]
Huang W
Shanghai Xu Hui District Central Hospital.
Chung Hua Hsin Hsueh Kuan Ping Tsa Chih 1990
Jun;18(3):155-6, 190
The effects of berberine on 100 cases with
ventricular tachyarrhythmias observed with 24 to
48 hour ambulatory monitoring were reported. The
results showed that 62% of patients had 50% or
greater, and 38% of patients had 90% or greater
VPC suppression. The mean value of VPCs in whole
group was significantly decreased by berberine
from 452 +/- 421.8 beats per hour to 271 +/- 352.7
beats per hour (P less than 0.001). These results
revealed that berberine is effective for
ventricular tachyarrhythmias. There were no severe
side effects, only mild gastroenterologic symptoms
were observed in some patients.
[Effects of berberine on ischemic
ventricular arrhythmia]
Huang WM, Wu ZD, Gan YQ
Chung Hua Hsin Hsueh Kuan Ping Tsa Chih 1989
Oct;17(5):300-1, 319
The effects of berberine on ischemic
ventricular arrhythmias induced by ligating the
left anterior descending coronary artery (LAD) of
canine were reported. The results showed that
berberine was able to get 99% suppression (P less
than 0.001) on the total ventricular premature
beats (VPCs) by 12 hours after ligature of LAD,
the paired VPCs, ventricular tachycardias and VPCs
with R on T were also significantly suppressed;
and the ventricular tachycardia induced by
programmed ventricular stimulation was effectively
inhibited by berberine. In addition, the results
revealed that the decrease of cardiac output
caused by ligature of LAD was obviously attenuated
by berberine. The mechanisms of the antiarrhythmic
effect of berberine on ischemic ventricular
tachyarrhythmias were discussed.
[Protective effects of berberine on
spontaneous ventricular fibrillation in dogs after
myocardial infarction]
Xu Z, Cao HY, Li Q
Chung Kuo Yao Li Hsueh Pao 1989
Jul;10(4):320-4
The effects of berberine (Ber 5 mg/kg iv) on
ventricular tachyarrhythmias and
electrophysiologic consequences in both normal and
ischemic myocardium were studied in the open-chest
dogs subjected to programmed electrical
stimulation (PES) and intimal surface an of the
circumflex coronary artery on 5-8 d after acute
myocardial infarction. Its effects were compared
with procainamide (PA). Both drugs distinctly
lengthened the QTc interval and the effective
refractory period (ERP) of normal and infarct
myocardium in both ventricles and decreased the
dispersion of ERP in infarct myocardium (IDR) as
well as the dispersion of ERP in left ventricle
(VDR). The PES-induced ventricular tachycardia
(VT) or ventricular fibrillation (VF) was
prevented in 4 out of 6 Ber treated and 5 out of 6
PA treated dogs. Ber prevented spontaneous VF in 4
dogs (n = 5). PA prevented spontaneous VF in 3
dogs (n = 5). Normal saline (NS) did not prevent
PES-induced VT/VF and spontaneous VF. The results
suggest that Ber may be effective in preventing
the onset of reentrant ventricular
tachyarrhythmias and sudden coronary death after
myocardial ischemic damage.
Protective effects of berberine and
phentolamine on myocardial reoxygenation
damage.
Huang Z, Chen S, Zhang G, Xu S, Huang W, Han Y,
Du X
Department of Cardiology, Changzheng Hospital,
Shanghai.
Chin Med Sci J 1992 Dec;7(4):221-5
The protective effects of berberine and
phentolamine against anoxia and reoxygenation
damage in isolated rat hrberine (24.5 mumol/L) in
both a noxic and aerobic perfusion media resulted
in a significant reduction of CPK release during
the reoxygenation period, and the ultrastructural
damage was reduced as compared with the control
group; the myocytes in the berberine-treated group
displayed mild intracellular edema,
well-registered myofibrils without contracted
bands, and swollen mitochondria with partially
broken cristae but without dense bodies. Berberine
did not inhibit calcium and sodium accumulation or
magnesium and potassium loss. Treatment with
phentolamine (6.6 mumol/L), an alpha-adrenoceptor
antagonist, had similar effects, though the CPK
release profile was shifted to the right and
downwards. These results suggest that although
berberine and phentolamine have some beneficial
effects on myocardial reoxygenation injury, they
may not abolish the injury. Therefore
alpha-adrenoceptor stimulation may not be the
major mechanism behind the injury.
Beneficial effects of berberine on
hemodynamics during acute ischemic left
ventricular failure in dogs.
Huang WM, Yan H, Jin JM, Yu C, Zhang H
Cardiovascular Research Laboratory, Xu Hui
District Central Hospital, Shanghai.
Chin Med J (Engl) 1992 Dec;105(12):1014-9
In 18 dogs ischemic left ventricular failure
characterized by a 30 percent reduction in peak
rate of rise of left ventricular pressure (+dp/dt)
and elevation of left ventricular end-diastolic
pressure (LVEDP) to 15 mmHg or more was produced
by ligation of the proximal left anterior
descending coronary artery followed by serial
occlusions of the distal left circumflex coronary
artery. In 10 days, administration of berberine in
an intravenous bolus injection (1 mg/kg, within 3
minutes) followed by a constant infusion (0.2
mg/kg/min, 30 minutes) increased the cardiac
output (CO) from 1.25 +/- 0.12 to 1.61 +/- 0.17
L/min (P < 0.05), and +dp/dt from 810 +/- 85 to
1021 +/- 130 mmHg/s (P < 0.01), and decreased
LVEDP from 16.5 +/- 1.3 to 12.0 +/- 1.0 mmHg (P
< 0.05), diaso 84 +/- 5 mmHg (P < 0.01),
syste mic vascular resistance from 7303 +/- 278 to
5442 +/- 231 dynes.x/cm5 (P < 0.01), but did
not affect the heart rate. Injection of 5% glucose
with the same volume did not improve CO and dp/dt
(P > 0.05) but increased the LVEDP from 17.1
+/- 1.4 to 17.8 +/- 1.6 mmHg (P < 0.01) in 8
dogs. The levels of plasma concentration of
berberine was determined with high-performance
liquid chromatography. The changes in plasma drug
level were found parallel to hemodynamic effects
of berberine. The results of this study showed
that berberine was able to improve the impaired
left ventricular function by its positive
inotropic effect and mild systemic
vasodilatation.
[The
role and mechanism of berberine on coronary
arteries]
Huang W
Xu Hui District Central Hospital, Shanghai.
Chung Hua Hsin Hsueh Kuan Ping Tsa Chih 1990
Aug;18(4):231-4, 254-5
Berberine increased coronary artery flow of
anesthetized open-chest canines and isolated
guinea pig hearts with ventricular fibrillation
induced by electric stimulus. The rabbits were
protected by berberine from ischemic ECG changes
caused by posterior pituitary hormones. Spasm of
isolated swine coronary arterial rings responded
to ergometrine was able to be prevented and
treated effectively by berberine. On isolated
swine coronary arterial strips, berberine shifted
norepinephrine cumulative dose-response curve
rightward parallelly without decreasing the
maximal response. The pA2 value was 6.7.
Contraction treatment effects post-PBMV, the
cardiac function tended to decline with time, the
decrease of ejection fraction, stroke volume and
cardiac output were 0.03 +/- 0.007, 5.44 +/- 1.04
ml and 0.44 +/- 0.08 L/min respectively. This
might be due to the unsuccessful control of
activity of rheumatism after PBMV and it is
necessary to pay attention to in the future.
Effect
of tincture of Crataegus on the LDL-receptor
activity of hepatic plasma membrane of rats fed an
atherogenic diet.
Rajendran S, Deepalakshmi PD, Parasakthy K,
Devaraj H, Devaraj SN
Department of Biochemistry, University of Madras,
India.
Atherosclerosis 1996 Jun;123(1-2):235-41
Tincture of Crataegus, (TCR), is a
hypocholesterolemic and antiatherosclerotic drug
made from berries of hawthorn, Crataegus
oxyacantha. Its main constituents are flavonoids,
triterpene saponins and a few cardioactive amines.
TCR, when administered simultaneously to rats fed
an atherogenic diet, significantly increased the
binding of 125I-LDL to the liver plasma membranes,
in vitro. Scatchard analysis of the specific
binding data revealed that under the influence o
to a greater number of 125I -LDL molecules
indicating an enhancement in the LDL-receptor
activity. TCR was also shown to increase bile acid
excretion and to depress hepatic cholesterol
synthesis in atherogenic diet fed rats. With these
observations in view, the hypocholesterolemic
action of TCR appears to be due to an upregulation
of hepatic LDL-receptors resulting in greater
influx of plasma cholesterol into the liver. TCR
also prevents the accumulation of cholesterol in
the liver by enhancing cholesterol degradation to
bile acids and by simultaneously suppressing
cholesterol biosynthesis. The various constituents
of TCR may act synergistically to bring about the
observed effects.
Effect
of a hawthorn extract on contraction and energy
turnover of isolated rat
cardiomyocytes.
Popping S, Rose H, Ionescu I, Fischer Y,
Kammermeier H
Institute of Physiology, Medical Faculty,
Rheinisch-Westfalische Technische Hochschule,
Aachen, Germany.
Arzneimittelforschung 1995 Nov;45(11):1157-61
The hawthorn extract LI 132 (crataegus),
prepared from leaves and flowers, and standardised
to 2.2% flavonoids, was investigated with respect
to its effect on
(1) the contraction,
(2) the energy-turnover and
(3) the apparent refractory period (t(ref)) of
isolated cardiac myocytes from adult rats.
(1) The contractile behaviour of attached
myocytes was analyzed by an image processing
system.
(2) The energy turnover was calculated from the
decrease in oxygen content in the myocyte
suspension, brought about by cellular respiration.
It was differentiated between energy turnover
related to cell shortening and that required for
ionic transport processes by application of the
contraction-inhibiting agent 2,3-butanedione
monoxime.
(3) The apparent refractory period (t(ref)) was
evaluaacing the myocytes with increasing
stimulation rates and determining the frequency at
which failure of single contractions occurred. For
these purposes, the myocytes were incubated in a
stimulation chamber, which is part of a
computer-assisted system allowing to
simultaneously evaluate the mechanics and
energetics of electrically induced contraction.
Within a range of 30-180 microg/ml, the hawthorn
extract exhibited a positive inotropic effect on
the contraction amplitude accompanied by a
moderate increase of energy turnover both for
mechanical and ionic processes. In comparison with
other positive inotropic interventions, such as
application of the beta-adrenergic agonist
isoprenaline, or of the cardiac glycoside ouabain
(g-strophantin), or elevation of the extracellular
Ca++-concentration, the effects of the hawthorn
extract were significantly more economical with
respect to the energetics of the myocytes.
Furthermore the extract prolonged the apparent
refractory period in the presence and the absence
of isoprenaline, which be indicative for an
antiarrhythmic potential.
[Crataegus Special Extract WS 1442.
Assessment of objective effectiveness in patients
with heart failure (NYHA II)]
Weikl A; Assmus KD; Neukum-Schmidt A; Schmitz
J; Zapfe G; Noh HS; Siegrist J
Hauptkrankenhaus Deggendorf.
Fortschr Med 1996 Aug 30;114(24):291-6
METHOD: In a multicenter, placebo-controlled
double-blind study, the efficacy of the
Crataegus-Specialextrakt WS 1442 in patients with
NYHA stage II cardiac insufficiency was
investigated. A total of 136 patients with this
diagnosis were admitted to the study and,
following a 2-week run-in phase, treated with
Crataegus-Specialextract or placebo over a period
of 8 weeks. The primary target parameter was the
change in the difference of the pressure, heart
rate product (systolic blood pressure x heart
rate/100) (PHRP 50 W load vs. rest) measured at
the beginning and end of treatment.
RESULTS: On the basis of this variable, a clear
improvement in the performance of the heart was
shown in the group receiving the test substance,
while the condition of the placebo group
progressively worsened. The therapeutic difference
between the groups was statistically significant.
The positive result for the objective efficacy
parameter was confirmed by a statistically obvious
superiority of Crataegus in the patient's own
assessment of improvement in the main symptoms
(reduced performance, shortness of breath, ankle
edema etc.). In addition, active treatment led, in
comparison with placebo, to a considerably better
quality of life for the patient, in particular
with respect to mental well-being. The
tolerability of the active substance proved to be
very good-as shown by comprehensive laboratory
investigations and the recording of undesirable
events.
CONCLUSION: All in all, the results of the
present clinical investigation confirm those of
previous studies showing that
Crataegus-Specialextrakt WS 1442 is an effective
and low-risk phytotherapeutic form of treatment in
patients with NYHA II cardiac insufficiency.
[Crataegus Special Extract WS 1442 in
NYHA II heart failure. A placebo controlled
randomized double-blind study]
Leuchtgens H
Fortschr Med 1993 Jul 20;111(20-21):352-4
In 30 patients with stage NYHA II cardiac
insufficiency, a placebo-controlled randomized
double-blind study was carried out to determine
the efficacy of the Crataegus special extract WS
1442. Treatment duration was 8 weeks, and the
substance was administered at a dose of 1 capsule
taken twice a day. The main target parameters were
alteration in the pressure-x-rate product (PRP)
under standardised loading on a bicycle ergometer,
and a score of subjective improvement of
complaints elicited by a questionnaire. Secondary
parameters were exercise tolerance and the change
in heart rate and arterial blood pressure. The
active substance group showed a statistically
significant advantage over placebo in terms of
changes in PRP (at a load of 50 W) and the score,
but also in the secondary parameter heart rate. In
both groups, systolic and diastolic blood pressure
was mildly reduced. No adverse reactions
occurred.
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