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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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