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Abnormal membrane concentrations of 20 and
22-carbon essential fatty acids: a common link between risk
factors and coronary and peripheral vascular disease?
Horrobin DF
Scotia Research Institute, Kentville, Nova Scotia,
Canada.
Prostaglandins Leukot Essent Fatty Acids 1995
Dec;53(6):385-96
Although elevated levels of cholesterol are associated with
increased risks of coronary and peripheral vascular disease,
the association frequently fails to provide a causative
explanation at the individual level. New hypotheses are
required which, whether or not they are correct, will provide
new lines of research. It is proposed here that the causes of
vascular disease are abnormal membrane phospholipid
concentrations of the 20-carbon and 22-carbon essential fatty
acids (EFAs) of the n-6 and n-3 series. These levels become
abnormal with ageing, with stress and in resp to smoking, high
cholesterol levels and high saturated fat intakes. They are
also abnormal in patients with diabetes and hypertension. The
effects of these EFAs and their metabolites include lowering
of triglycerides, elevation of high-density lipoprotein
(HDL)-cholesterol, reduction of blood pressure,
vasodilatation, reduction of fibrinogen levels and inhibition
of platelet aggregation and of cardiac arrhythmias.
Prospective studies have shown that abnormal levels of these
fatty acids are predictive of future coronary death.
Controlled trials of treatment have demonstrated that
provision of the fatty acids reduces both coronary and total
mortality. Further experimental and clinical investigations of
the roles of appropriate membrane concentrations of these
fatty acids are justified. (157 Refs.)
Differential changes in left and right ventricular
adenylyl cyclase activities in congestive heart failure
Sethi R, Dhalla KS, Beamish RE, Dhalla NS
Institute of Cardiovascular Sciences, St. Boniface General
Hospital Research Centre, Faculty of Medicine, University of
Manitoba, Winnipeg, Canada.
Am J Physiol 1997 Feb;272(2 Pt 2):H884-93
The status of beta-adrenergic receptors and adenylyl
cyclase in crude membranes from both left and right ventricles
was examined when the left coronary artery in rats was
occluded for 4, 8, and 16 wk. The adenylyl cyclase activity in
the presence of isoproterenol was decreased in the uninfarcted
(viable) left ventricle and increased in the right ventricle
subsequent to myocardial infarction. The density of
beta1-adrenergic receptors, unlike beta2-receptors, was
reduced in the left ventricle, whereas no change in the
characteristics of beta1- and beta2-adrenergic receptors was
seen in the right ventricle. The catalytic activity of
adenylyl cyclase was depressed in the viable left ventricle
but was unchanged in the right ventricle. In comparison to
sham controls, the basal, as well as NaF-, forskolin-, and
5'-guanylyl imidodiphosphate (Gpp(NH)p)-stimulated adenylyl
cyclase activities were decreased in the left ventricle and
increased in the right ventricle of the experimental animals.
Opposite alterations in the adenylyl cyclase activities in
left and right ventricles from infarcted animals were also
seen when two types of purified sarcolemmal preparations were
employed. These changes in adenylyl cyclase activities in the
left and right ventricles were dependent on the degree of
heart failure. Furthermore, adenosine 3',5'-cyclic
monophosphate contents were higher in the right ventricle and
lower in the left ventricle from infarcted animals injected
with saline, isoproterenol, or forskolin in comparison to the
controls. The results suggest differential changes in the
viable left and right ventricles with respect to adenylyl
cyclase activities during the development of congestive heart
failure due to myocardial infarction.
Chronic opiate-receptor inhibition in experimental
congestive heart failure in dogs
Yatani A, Imai N, Himura Y, Suematsu M, Liang CS
Department of Medicine, University of Rochester Medical
Center, New York 14642, USA.
Am J Physiol 1997 Jan;272(1 Pt 2):H478-84
Acute administration of opiate-receptor antagonists has
previously been shown to improve cardiac output, sortie blood
pressure, systolic ventricular performance, and the baroreflex
function in conscious dogs with right-sided congestive heart
failure (RHF). However, whether similar changes occur after
chronic opiate-receptor inhibition in congestive heart failure
is not known. To determine the chronic effects of
opiate-receptor antagonism on RHF, we administered naltrexone
(200 mg/day), a long-acting, orally active opiate- receptor
blocking agent, to RHF and sham-operated animals for 6 wk.
Naltrexone had no effects on resting heart rate, right atrial
pressure, aortic pressure, or cardiac output in RHF dogs but
increased the first derivative of right and left ventricular
pressure with respect to time (dP/dt) at rest and improved the
dP/dt responses to isoproterenol. The inotropic responses to
isoproterenol and forskolin in isolated right
ventricular trabeculate muscle also were improved by chronic
naltrexone in RHF. Myocardial beta-receptor density was
reduced in the failing right ventricle compared with the
control (58 plus or minus 3 vs. 108 plus or minus 6 fmol/mg
protein, P < 0.01) but was unaffected by addition of
naltrexone. Finally, naltrexone prevented the decline in
baroreflex sensitivity that occurred in RHF (-0.2 plus or
minus 0.5 vs. -6.0 plus or minus 0.5 ms/mmHg, P < 0.01).
These effects of naltrexone did not occur in the sham-operated
animals. Chronic opiate-receptor blockade with naltrexone
attenuates the development of reduced adrenergic inotropic
responsiveness and barereflex subsensitivity that occur in
RHF. Because there was a similar improvement in the forskolin
response in the absence of significant alterations in
myocardial beta-adrenoceptor density after naltrexone
treatment, the improvement in adrenergically mediated
inotropic effects probably is mediated via a postreceptor
mechanism.
beta-adrenoceptor mediated signal transduction in
congestive heart failure in cardiomyopathic (UM-X7.1)
hamsters
Kaura D, Takeda N, Sethi R, Wang X, Nagano M, Dhalla NS
Division of Cardiovascular Sciences, St. Boniface General
Hospital Research Centre, Winnipeg, Manitoba, Canada.
Mol Cell Biochem 1996 Apr 12-26;157(1-2):191-6
In view of the lack of information regarding the status of
beta-adrenoceptor mediated signal transduction mechanisms at
severe stages of congestive heart failure, the status of
beta-adrenoceptors, G-proteins and adenylyl cyclase activities
was examined in 220-275 day old cardiomyopathic hamster
hearts. Although no changes in the Kd values for beta1- and
beta2,-adrenoceptors were seen, the number of
beta1-adrenoceptors, unlike that of beta2-adrenoceptors, was
markedly decreased in cardiac membranes from failing hearts.
The activation of adenylyl cyclase in the failing hearts by
different concentrations of isoproterenol was also attenuated
in comparison to the control preparations. The basal adenylyl
cyclase activity in cardiac membranes from the failing hearts
was not altered; however, the stimulated enzyme activities,
when measured in the presence of forskolin, NaF or
Gpp(NH)p were depressed significantly. The functional activity
of Gs-proteins (measured by cholera toxin stimulation of
adenylyl cyclase) was depressed whereas that of Gi-proteins
(measured by pertussis toxin stimulation of adenylyl cyclase)
was increased in the failing hearts. Not only were the Gs- and
Gi-protein contents (measured by immunoblotting) increased,
the bioactivities of these proteins as determined by
ADP-ribosylations in the presence of cholera toxin and
pertussis toxin, respectively, were also higher in failing
hearts in comparison to the control values. Northern blot
analysis revealed that the signals for Gs- and Gi-protein
mRNAs were augmented at this stage of heart failure. These
results indicate that the loss of adrenergic support at severe
stages of congestive heart failure in cardiomyopathic hamsters
may involve a reduction in the number of beta1-adrenoceptors,
and an increase in Gi-protein contents as well as
bioactivities in addition to an uncoupling of Gs-proteins from
the catalytic site of adenylyl cyclase in cardiac
membrane.
Pharmacology and inotropic potential of forskolin
in the human heart.
Bristow MR, Ginsburg R, Strosberg A, Montgomery W, Minobe
W
J Clin Invest 1984 Jul;74(1):212-23
We evaluated the effects of the diterpene compound
forskolin in human myocardial adenylate cyclase preparations,
isolated trabeculae and capillary muscles derived from failing
human hearts, and acutely instrumented dogs. forskolin was a
potent, powerful activator of human myocardial adenylate
cyclase and produced maximal effects that were 4.82 (normally
functioning left ventricle) and 6.13 (failing left ventricle)
fold greater than isoproterenol. In contrast to isoproterenol,
forskolin retained full activity in membrane preparations
derived from failing hearts. In cyclase preparations,
forskolin demonstrated unique substrate and Mg2+ kinetic
properties that could be distinguished from hormone
receptor-coupled agonists or fluoride ion. The adenylate
cyclase stimulatory effect of forskolin was synergistic with
isoproterenol, apparently due to the location of forskolin
activation being beyond the level of hormone receptor-agonist
in the receptor-cyclase complex. Forskolin was a potent
positive inotrope in failing human myocardium, producing a
stimulation of contraction that was similar to isoproterenol.
Finally, in open chest dogs Forskolin was a positive inotropic
agent that reduced preload and afterload. We conclude that
forskolin belongs to a class of agents that may have
therapeutic potential in the treatment of congestive heart
failure.
[Effects of forskolin on canine congestive heart
failure]
Sonoki H, Uchida Y, Masuo M, Tomaru T, Katoh A, Sugimoto
T
Nippon Yakurigaku Zasshi 1986 Nov;88(5):389-94
Forskolin is a diterpene of the labdane family which
activates adenylate cyclase. The effects of forskolin were
investigated in a congestive heart failure (CHF) model that we
newly established using anesthetized dogs. The model was made
by the intramural injection of protease into the left
ventricular free wall, saline loading, and dextran and
methoxamine infusion. By this maneuver, aortic blood flow
(AoBF) was decreased; left atrial pressure (LAP), systemic
vascular resistance (SVR) and left ventricular endodiastolic
pressure (LVEDP) were markedly increased; and systemic blood
pressure was unchanged. A bolus injection of 5.0 micrograms/kg
forskolin reversed the hemodynamic findings of CHF. It reduced
LAP (17.5----7.9 mmHg) (mean, N = 7), SVR (19980----10390 dyne
sec/cm5), time constant T (90.7----59.2 msec) and LVEDP
(22.8----16.8 mmHg); and it increased Vmax (2.32----2.82
l/sec) and AoBF (0.50----0.72 l/min). Forskolin improved the
CHF mainly through its vasodilator and positive inotropic
actions.
Italian multicenter study on the safety and
efficacy of coenzyme Q10 as adjunctive therapy in heart
failure. CoQ10 Drug Surveillance Investigators.
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino
G
Department of Internal Medicine, V. Buzzi Hospital, Reggio
Emilia.
Mol Aspects Med 1994;15 Suppl:s287-94
Digitalis, diuretics and vasodilators are considered the
standard therapy for patients with congestive heart failure,
for which treatment is tailored according to the severity of
the syndrome and the patient profile. Apart from the clinical
seriousness, heart failure is always characterized by an
energy depletion status, as indicated by low intramyocardial
ATP and coenzyme Q10 levels. We investigated safety and
clinical efficacy of Coenzyme Q10 (CoQ10) adjunctive treatment
in congestive heart failure which had been diagnosed at least
6 months previously and treated with standard therapy. A total
of 2664 patients in NYHA classes II and III were enrolled in
this open noncomparative 3-month postmarketing study in 173
Italian centers. The daily dosage of CoQ10 was 50-150 mg
orally, with the majority of patients (78%) receiving 100
mg/day. Clinical and laboratory parameters were evaluated at
the entry into the study and on day 90; the assessment of
clinical signs and symptoms was made using from two-to
seven-point scales. The results show a low incidence of side
effects: 38 adverse effects were reported in 36 patients
(1.5%) of which 22 events were considered as correlated to the
test treatment. After three months of test treatment the
proportions of patients with improvement in clinical signs and
symptoms were as follows: cyanosis 78.1%, oedema 78.6%,
pulmonary rales77.8%, enlargement of liver area 49.3%, jugular
reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating
79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo
73.1% and nocturia 53.6%. Moreover we observed a contemporary
improvement of at least three symptoms in 54% of patients;
this could be interpreted as an index of improved quality of
life.
[Coenzyme Q10 (ubiquinone) in the treatment of
heart failure. Are any positive effects documented?]
Spigset O
Avdelningen for klinisk farmakologi, Norrlands
Universitetssjukhus, Umea.
Tidsskr Nor Laegeforen 1994 Mar 20;114(8):939-42
Coenzyme Q10 is an endogenous substance which has a well
established role as electron carrier in the mitochondrial
synthesis of adenosine triphosphate (ATP). In addition,
coenzyme Q10 also has antioxidant and membrane stabilizing
properties. Based on biopsy samples from patients undergoing
cardiac surgery and blood samples from patients with
congestive heart failure, the existence of a relative Q10
deficiency in patients with cardiac failure has been
suggested. A total number of eight double blind, placebo
controlled studies in patients with heart failure have been
published. Most of these studies include a small number of
patients, and various methodological problems have been
attributed to these. The results, judged as improvement in
ejection fraction or work capacity, are inconsistent. In one
large study, Coenzyme Q10 was found to have a positive effect
on morbidity, and in another on quality of life. However,
although some of the results appear to be promising, more
studies are needed, including studies designed with mortality
as a primary end point, before the effect of the substance in
patients with heart failure can be established. (30 Refs.)
Italian multicenter study on the safety and
efficacy of coenzyme Q10 as adjunctive therapy in heart
failure (interim analysis). The CoQ10 Drug Surveillance
Investigators.
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino
G
Department of Internal Medicine, V. Buzzi Hospital,
Milan.
Clin Investig 1993;71(8 Suppl):S145-9
Digitalis, diuretics, and vasodilators are considered
standard therapy for patients with congestive heart failure,
for which treatment is tailored according to the severity of
the syndrome and the patient profile. Apart from the clinical
seriousness, heart failure is always characterized by an
energy depletion status, as indicated by low intramyocardial
ATP and coenzyme Q10 levels. We investigated safety and
clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment
in congestive heart failure, which had been diagnosed at least
6 months previously and treated with standard therapy. A total
of 2500 patients in NYHA classes II and III were enrolled in
this open noncomparative 3-month postmarketing drug
surveillance study in 173 Italian centers. The daily dose of
CoQ10 was 50-150 mg orally, with the majority of patients
(78%) receiving 100 mg/day. Clinical and laboratory parameters
were evaluated at the entry into the study and on day 90; the
assessment of clinical signs and symptoms was made using from
two- to seven-point scales. Preliminary results on 1113
patients (mean age 69.5 years) show a low incidence of side
effects: 10 adverse reactions were reported in 8 (0.8%)
patients, of which only 5 reactions were considered as
correlated to the test treatment. After 3 months of test
treatment the proportions of patients with improvement in
clinical signs and symptoms were as follows: cyanosis 81%,
edema 76.9%, pulmonary rales 78.4%, enlargement of the liver
area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations
75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo
73%, and nocturia 50.7%.
Isolated diastolic dysfunction of the myocardium
and its response to CoQ10 treatment.
Langsjoen PH, Langsjoen PH, Folkers K
Clin Investig 1993;71(8 Suppl):S140-4
Symptoms of fatigue and activity impairment, atypical
precordial pain, and cardiac arrhythmia frequently precede by
years the development of congestive heart failure. Of 115
patients with these symptoms, 60 were diagnosed as having
hypertensive cardiovascular disease, 27 mitral valve prolapse
syndrome, and 28 chronic fatigue syndrome. These symptoms are
common with diastolic dysfunction, and diastolic function is
energy dependent. All patients had blood pressure, clinical
status, Coenzyme Q10 (CoQ10) blood levels and
echocardiographic measurement of diastolic function, systolic
function, and myocardial thickness recorded before and after
CoQ10 replacement. At control, 63 patients were functional
class III and 54 class II; all showed diastolic dysfunction;
the mean CoQ10 blood level was 0.855 micrograms/ml; 65%, 15%,
and 7% showed significant myocardial hypertrophy, and 87%,
30%, and 11% had elevated blood pressure readings in
hypertensive disease, mitral valve prolapse and chronic
fatigue syndrome respectively. Except for higher blood
pressure levels and more myocardial thickening in the
hypertensive patients, there was little difference between the
three groups. CoQ10 administration resulted in improvement in
all; reduction in high blood pressure in 80%, and improvement
in diastolic function in all patients with follow-up
echocardiograms to date; a reduction in myocardial thickness
in 53% of hypertensives and 36% of the combined prolapse and
fatigue syndrome groups; and a reduced fractional shortening
in those high at control and an increase in those initially
low.
Effect of coenzyme Q10 therapy in patients with
congestive heart failure: a long-term multicenter randomized
study.
Morisco C, Trimarco B, Condorelli M
Facolta di Medicina e Chiruriga, Universita degli Studi di
Napoli Federico II.
Clin Investig 1993;71(8 Suppl):S134-6
The improved cardiac function in patients with congestive
heart failure treated with coenzyme Q10 supports the
hypothesis that this condition is characterized by
mitochondrial dysfunction and energy starvation, so that it
may be ameliorated by Coenzyme Q10 supplementation. However,
the main clinical problems in patients with congestive heart
failure are the frequent need of hospitalization and the high
incidence of life-threatening arrhythmias, pulmonary edema,
and other serious complications. Thus, we studied the
influence of Coenzyme Q10 long-term treatment on these events
in patients with chronic congestive heart failure (New York
Heart Association functional class III and IV) receiving
conventional treatment for heart failure. They were randomly
assigned to receive either placebo (n = 322, mean age 67
years, range 30-88 years) or COENZYME Q10 (n = 319, mean age
67 years, range 26-89 years) at the dosage of 2 mg/kg per day
in a 1-year double-blind trial. The number of patients who
required hospitalization for worsening heart failure was
smaller in the Coenzyme Q10 treated group (n = 73) than in the
control group (n = 118, P < 0.001). Similarly, the episodes
of pulmonary edema or cardiac asthma were reduced in the
control group (20 versus 51 and 97 versus 198, respectively;
both P < 0.001) as compared to the placebo group. Our
results demonstrate that the addition of coenzyme Q10 to
conventional therapy significantly reduces hospitalization for
worsening of heart failure and the incidence of serious
complications in patients with chronic congestive heart
failure.
Role of metabolic therapy in cardiovascular
disease.
Rengo F, Abete P, Landino P, Leosco D, Covelluzzi F, Vitale
D, Fedi V, Ferrara N
Istituto di Medicina Interna, Cardiologia e Chirurgia
Cardiovascolare, Catiedra di Geriatria, Facolta di Medicina,
Napoli.
Clin Investig 1993;71(8 Suppl):S124-8
The pathophysiological basis for the use of metabolic
therapy in the treatment of heart failure is analyzed.
Bioenergetical processes related to ATP bioavailability play a
central role in regulating myocardial contractility at rest
and on effort. Furthermore, a significant correlation has been
demonstrated in diseased heart between ATP content, revealed
at endomyocardial biopsy, and systolic and diastolic left
ventricular indexes evaluated with invasive and noninvasive
methods. Several international investigations demonstrate the
beneficial effects of ubiquinone (Coenzyme Q10) in the
treatment of heart failure. Here the results of a study are
reported that was conducted on patients with heart failure
treated with ubiquinone. After 7 months of oral drug
administration (100 mg/day), a significant improvement was
observed in echocardiographic indexes of systolic function,
cardiothoracic ratio, and clinical signs and symptoms of
congestive heart failure. In conclusion, the introduction of
metabolic drugs, such as ubiquinone, in the treatment of heart
failure opens new horizons in the therapeutic approach to an
ailment that entails substantial human and social costs.
Usefulness of taurine in chronic congestive heart
failure and its prospective application.
Azuma J, Sawamura A, Awata N
Third Department of Internal Medicine, Osaka University
Medical School, Japan.
Jpn Circ J 1992 Jan;56(1):95-9
We compared the effect of oral administration of taurine (3
g/day) and coenzyme Q10 (CoQ10) (30 mg/day) in 17 patients
with congestive heart failure secondary to ischemic or
idiopathic dilated cardiomyopathy, whose ejection fraction
assessed by echocardiography was less than 50%. The changes in
echocardiographic parameters produced by 6 weeks of treatment
were evaluated in a double-blind fashion. In the
taurine-treated group significant treatment effect was
observed on systolic left ventricular function after 6 weeks.
Such an effect was not observed in the CoQ10-treated
group.
Co-enzyme Q10: a new drug for cardiovascular
disease.
Greenberg S, Frishman WH
Department of Medicine, Mt. Sinai Hospital and Medical
Center, New York, New York.
J Clin Pharmacol 1990 Jul;30(7):596-608
Co-enzyme Q10 (ubiquinone) is a naturally occurring
substance which has properties potentially beneficial for
preventing cellular damage during myocardial ischemia and
reperfusion. It plays a role in oxidative phosphorylation and
has membrane stabilizing activity. The substance has been used
in oral form to treat various cardiovascular disorders
including angina pectoris, hypertension, and congestive heart
failure. Its clinical importance is now being established in
clinical trails worldwide. (133 Refs.)
Coenzyme Q10: a new drug for myocardial
ischemia?
Greenberg SM, Frishman WH
Department of Medicine, Mt. Sinai Hospital and Medical
School, New York, New York
Med Clin North Am 1988 Jan;72(1):243-58
A biochemical rationale for using CoQ in treating certain
cardiovascular diseases has been established. CoQ subserves an
endogenous function as an essential cofactor in several
metabolic pathways, particularly oxidative respiration. As an
exogenous source in supraphysiologic doses, CoQ may have
pharmacologic effects that are beneficial to tissues rendered
ischemic and then reperfused. Its mechanism of action appears
to be that of a free radical scavenger and/or direct membrane
stabilizer. Initial clinical studies performed abroad and in
the United States indicate that CoQ may be effective in
treating certain patients with ischemic heart disease,
congestive heart failure, toxin-induced cardiotoxicity, and
possibly hypertension. The most intriguing property of CoQ is
its potential to protect and preserve ischemic myocardium
during surgery. Currently, CoQ is still considered an
experimental agent and only further studies will determine
whether it will be useful therapy for human cardiovascular
disease states. (105 Refs.)
Cardiac performance and Coenzyme Q10 in thyroid
disorders
Suzuki H, Naitoh T, Kuniyoshi S, Banba N, Kuroda H, Suzuki Y,
Hiraiwa M, Yamazaki N, Ishikawa M, Hashigami Y, et al
Endocrinol Jpn 1984 Dec;31(6):755-61
To investigate the relationship between serum levels of
Coenzyme Q10 and cardiac performance in thyroid disorders, we
studied the cardiac performance and assessed serum levels of
thyroid hormones and Coenzyme Q10 in 20 patients with
hyperthyroidism, 5 patients with hypothyroidism and 10 normal
subjects. A significant inverse correlation between thyroid
hormones and Coenzyme Q10 levels was found by performing
partial correlation analysis. Because low serum levels of
Coenzyme Q10 were found in thyrotoxic patients and congestive
heart failure may occur as a result of severe hyperthyroidism,
120 mg of Coenzyme Q10 was administered daily for one week to
12 hyperthyroid patients and the change in cardiac performance
was assessed. Further augmentation of cardiac performance was
found in hyperthyroid hearts, which were already augmented,
after the administration of Coenzyme Q10. It appears,
therefore, that the Coenzyme Q10 dose actually has a
therapeutic value for congestive heart failure induced by
severe thyrotoxicosis.
A clinical study of the effect of Coenzyme Q on
congestive heart failure.
Ishiyama T, Morita Y, Toyama S, Yamagami T, Tsukamoto N
Jpn Heart J 1976 Jan;17(1):32-42
Expecting activation of myocardial energy liberation,
COENZYME Q was applied as a treatment to 55 patients suffering
from congestive heart failure. Daily doses of 50 to 100 mg of
coenzyme Q7 were injected intravenously in 21 cases for 3 to
35 days. Daily doses of 60 mg of coenzyme Q7 were administered
perorally in 17 cases for 14 to 196 days. Daily doses of 30 mg
of Coenzyme Q10 were administered perorally in 17 cases for 7
to 182 days. Clinical effects were evaluated within 4 weeks by
the criteria using a scoring method of severity of congestive
heart failure which was devised by the authors. In summary a
certain effect was found in 20 cases and a mild effect was
observed in 29 cases. No significant changes were observed in
heart rate and blood pressure. Exanthema appeared in 2
patients of the group of COENZYME Q7 intravenous injection. In
conclusion the therapeutic effect of COENZYME Q was thought to
be mild but stable in supplement to digitalis therapy in cases
of congestive heart failure.
[Magnesium in cardiology]
Weiss M
Medizinische Abteilung, Inselspital Bern.
Schweiz Rundsch Med Prax 1995 May
2;84(18):526-32
Magnesium acts as a cofactor of numerous enzymes and is
important for the maintenance of a high intracellular
potassium concentration and the transmembrane action
potential. Of the total magnesium content of about 1000 mmol,
only 0.3% are located in plasma. Hypomagnesemia and probable
magnesium deficiency are found in 7 to 11% of hospitalized
patients but are only rarely accompanied by relevant clinical
symptoms. Prolonged diuretic therapy and secondary
aldosteronism are frequent causes of hypomagnesemia in
cardiology. Intravenous magnesium is a vasodilatator and
prolongs the AH interval. In animal studies magnesium has been
shown to have cardioprotective and platelet-inhibiting
properties. The only verified indication for intravenous
magnesium is the initial treatment of torsade de pointes.
Magnesium may suppress digitalis-induced tachyarrhythmias and
convert paroxysmal supraventricular tachycardia and
monomorphic ventricular tachycardia to sinus rhythm. Its role
in the treatment of acute myocardial infarction and of
ventricular arrhythmias in congestive heart failure is
unclear. (81 Refs.)
Magnesium therapy in acute myocardial infarction
when patients are not candidates for thrombolytic
therapy
Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz
B
Heart Institute, Sheba Medical Center, Tel-Hashomer,
Israel.
Am J Cardiol 1995 Feb 15;75(5):321-3
Thrombolytic therapy reduces in-hospital mortality.
However, 70% to 80% of patients do not receive thrombolysis
and their in-hospital mortality is high. During the last
decade some clinical trials demonstrated that magnesium
sulfate reduced in-hospital mortality. The aim of this study
was to evaluate the effects of magnesium sulfate in patients
with acute myocardial infarction (AMI) who were considered
unsuitable for thrombolytic therapy. Intravenous magnesium
sulfate was evaluated in 194 patients with AMI ineligible for
thrombolytic therapy in a randomized, double-blind,
placebo-controlled study. Group I consisted of 96 patients who
received 48-hour intravenous magnesium. Group II consisted of
98 patients who received isotonic glucose as a placebo.
Magnesium reduced the incidence of arrhythmias, congestive
heart failure, and conduction disturbances compared with
placebo (27% vs 40%, p = 0.04; 18% vs 23%, p = 0.27; 10% vs
15%, p = 0.21, respectively). Left ventricular ejection
fraction 72 hours and 1 to 2 months after admission was higher
in patients who received magnesium sulfate than in those
taking placebo (49% vs 43% and 52% vs 45%; p = 0.01,
respectively). In-hospital mortality was significantly reduced
in patients receiving magnesium sulfate than in those
receiving placebo (4% vs 17%; p < 0.01), and also in the
subgroup of elderly patients (> 70 years) (9% vs 23%; p =
0.09). In conclusion, magnesium sulfate should be considered
as an alternative therapy to thrombolysis in patients with
AMI.
[Oral magnesium supplementation to patients
receiving diuretics--normalization of magnesium, potassium and
sodium, and potassium pumps in the skeletal muscles]
Dorup I, Skajaa K, Thybo NK
Aarhus Universitet, Fysiologisk Institut.
Ugeskr Laeger 1994 Jul 4;156(27):4007-10, 4013
In 76 consecutive patients who had received diuretics for
1-17 years for arterial hypertension or congestive heart
failure, muscle concentrations of magnesium, potassium, and
sodium-potassium pumps were significantly reduced compared to
31 age- and sex-matched controls. Thirty-six patients with
muscle magnesium and/or potassium below the control level
received oral magnesium hydroxide supplement for 2-12 weeks (N
= 20) or 26 weeks (N = 16). After short term (2-12 weeks)
magnesium supplementation muscle parameters were increased,
but far from normalized. After magnesium supplementation for
26 weeks, the muscle concentrations of magnesium, potassium
and sodium-potassium pumps were normalized in most cases. Oral
magnesium supplementation may restore diuretic-induced
disturbances in the concentrations of magnesium, potassium and
sodium-potassium pumps in skeletal muscle. A supplemental
period of at least six months seems required before complete
normalization can be expected.
Effects of intravenous magnesium sulfate on
arrhythmias in patients with congestive heart failure.
Gottlieb SS, Fisher ML, Pressel MD, Patten RD, Weinberg M,
Greenberg N
Division of Cardiology, University of Maryland School of
Medicine, Baltimore 21201.
Am Heart J 1993 Jun;125(6):1645-50
Intravenous magnesium is an effective treatment for
ventricular tachycardia of some etiologies, and in patients
with congestive heart failure low serum magnesium
concentrations are associated with frequent arrhythmias and
high mortality. This suggests that magnesium administration
may decrease the frequency of ventricular arrhythmias in
patients with heart failure. We therefore assessed the impact
of an intravenous magnesium infusion upon the frequency of
ventricular premature depolarizations in 40 patients with New
York Heart Association (NYHA) class II to IV heart failure and
serum magnesium < or = 2.0 mg/dl. Within 1 week of a
baseline 6-hour ambulatory electrocardiographic recording, an
infusion of 0.2 mEq/kg of MgSO4 was given over 1 hour and a
repeat 6-hour recording was obtained. There was an inverse
relationship between the change in magnesium concentration and
the change in frequency of premature ventricular
depolarizations; premature ventricular depolarizations
declined by 134 +/207 hr-1 in patients in whom serum magnesium
concentration increased > or = 0.75 mg/dl, but increased by
72 +/- 393 hr-1 in patients with a change < 0.75 mg/dl (p
< 0.05). For all patients, the frequency of premature
ventricular depolarizations was 283 +/- 340 hr-1 pretreatment
and 220 +/269 hr-1 following magnesium infusion (p = 0.21).
Patients with > or = 300 premature ventricular
depolarizations hr-1 demonstrated a decrease from 794 +/- 309
to 369 +/- 223 hr-1 (p < 0.001). Intravenous magnesium
administration decreased the frequency of couplets from 233
+/- 505 to 84 +/- 140 (p < 0.05).(ABSTRACT TRUNCATED AT 250
WORDS)
Magnesium-potassium interactions in cardiac
arrhythmia. Examples of ionic medicine.
Iseri LT, Ginkel ML, Allen BJ, Brodsky MA
College of Medicine University of California, Irvine.
Magnes Trace Elem 1991-92;10(2-4):193-204
Ionic biology involving Ca2+, Na+, K+ and Mg2+ across the
cell membrane and in the development of the action potential
is reviewed with reference to cardiac arrhythmia. K+ and Mg2+
deficiency which frequently occur together lead to abnormal
ionic transfer of Na+, K+ and Ca2+ with development of
automaticity, triggered impulses and reentrant tachycardia.
Tachycardia occurring in acute myocardial ischemia, congestive
heart failure, hypertensives on diuretics and digitalis
toxicity is examined according to the concept of ionic
imbalance. A protocol for prevention and treatment of cardiac
tachyarrhythmia is proposed with this concept in mind.
Clinical clues to magnesium deficiency.
Cohen L, Kitzes R
Department of Medicine B, Lady Davis Carmel Hospital, Haifa,
Israel.
Isr J Med Sci 1987 Dec;23(12):1238-41
Two cases of congestive heart failure with coexistent
magnesium and potassium depletion are described. The prolonged
QTc intervals and ventricular premature beats of the first
patient and the idionodal tachycardia of the second patient
disappeared only after magnesium repletion, which normalized
both extra- and intracellular potassium and magnesium levels.
The third patient had a case of urosepsis while on total
parenteral nutrition. He developed diarrhea, hypocalcemia,
hypokalemia, hypomagnesemia, weakness, muscular fasciculations
and athetoid movements. The neurological manifestations were
relieved and the biochemical abnormalities normalized only
after magnesium repletion.
Platelet taurine in patients with arterial
hypertension, myocardial failure or infarction.
Paasonen MK, Penttila O, Himberg JJ, Solatunturi E
Acta Med Scand Suppl 1980;642:79-84
The content of taurine in the hypertrophied left ventricle
is increased in congestive heart failure an in spontaneously
hypertensive (SH) rats. In SH rats the taurine content of and
taurine uptake by the platelets are also increased. The
present results indicate that, as in the heart, the taurine
content may also increase in the platelets of those patients
with congestive heart failure. The taurine content and uptake
are not increased in the platelets of hypertensive patients as
they are in the platelets of SH rats. It is likely that in
acute myocardial infarction, a considerable amount of taurine
is released from the heart into the plasma. However, there is
no simultaneous increase in the platelet taurine content. From
this work on can only conclude that platelets may reflect
taurine changes in the heart in some pathological states, e.g.
congestive heart failure.
Physiological and experimental regulation of
taurine content in the heart.
Huxtable RJ, Chubb J, Azari J
Fed Proc 1980 Jul;39(9):2685-90
High concentrations of taurine are found in the heart and
these are increased still further in congestive heart failure.
It appears that taurine is largely derived by influx from the
circulation, and this influx is stimulated by cyclic AMP,
whereas influx of alpha-amino acids is unaffected. Influx
occurs via a saturable transport system that has strict
requirements for ligands. Other substances are transported by
this system, including beta-alanine, hypotaurine, guanidoethyl
sulfonate, and, to a lesser extent, guanidinopropionate; and
these are competitive antagonists for taurine transport.
Guanidinoethyl sulfonate, in vivo, markedly lowers taurine
concentrations over the course of a few days in all tissues
examined in the rat and mouse (but not in the guinea pig). The
concentrations of other amino acids are unaffected.
Guanidinoethyl sulfonate may prove to be a useful substance in
the study of the biological role of taurine, in view of its
ability to regulate taurine content in a number of species.
Despite the numerous pharmacological actions of taurine, its
physiological function in the heart remains problematic. One
function appears to be the modulation of calcium movements.
The inotropic actions of taurine and beta-adrenergic
activation may be linked via the cyclic AMP-dependent
regulation of taurine influx.
A relation between myocardial taurine contest and
pulmonary wedge pressure in dogs with heart failure.
Newman WH, Frangakis CJ, Grosso DS, Bressler R
Physiol Chem Phys 1977;9(3):259-63
Myocardial taurine levels were correlated with pulmonary
wedge pressure (PWP) in dogs with congestive heart failure
(CHF). Heart failure was induced by creating an infrarenal
aortocaval fistula. PWP ranged from 6.6 to 28 mm Hg,
suggesting a wide range in severity of heart failure in those
dogs. Compared to taurine levels of normal dogs, levels of the
CHF group were significantly elevated in both left and right
ventricles. Linear regression analysis of ventricular taurine
content yielded a highly significant direct relation to PWP.
The results suggest that myocardial taurine content increases
as heart failure becomes more severe.
Adrenergic stimulation of taurine transport by the
heart.
Huxtable R, Chubb J
Science 1977 Oct 28;198(4315):409-11
A high-affinity transport system that is specific for
beta-amino acids has been delineated in rat hearts. This
system transports the cardiotonic sulfonic amino acid taurine.
beta-Adrenergic stimulation increases the transport capacity
without effect on alpha-amino acid uptake, as does stimulation
with adenosine 3',5'-monophosphate or theophylline. The
existence of such an uptake system for taurine in the heart
accounts for the high intra- to extracellular concentration
gradient that is maintained, and suggests that cardiac stress
is associated with increased taurine uptake. This may explain
why taurine is the only amino acid to be markedly elevated in
congestive heart failure. taurine is a modifier of calcium
fluxes in the heart, as are beta-adrenergic agonists. The
presence of this uptake system suggests a link between
beta-adrenergic stimulation of calcium and taurine fluxes.
Effects of L-Carnitine administration on left
ventricular remodeling after acute anterior myocardial
infarction
Iliceto S, Scrutinio D, Bruzzi P, D'Ambrosio G, Boni L, Di
Biase M, Biasco G, Hugenholtz PG, Rizzon P
Institute of Cardiology, University of Bari, Italy.
J Am Coll Cardiol 1995 Aug;26(2):380-7
OBJECTIVES. This study was performed to evaluate the
effects of L-Carnitine administration on long-term left
ventricular dilation in patients with acute anterior
myocardial infarction.
BACKGROUND. Carnitine is a physiologic compound that
performs an essential role in myocardial energy production at
the mitochondrial level. Myocardial Carnitine deprivation
occurs during ischemia, acute myocardial infarction and
cardiac failure. Experimental studies have suggested that
exogenous Carnitine administration during these events has a
beneficial effect on function.
METHODS. The L-Carnitine Ecocardiografia Digitalizzata
Infarto Miocardico (CEDIM) trial was a randomized,
double-blind, placebo-controlled, multicenter trial in which
472 patients with a first acute myocardial infarction and high
quality two-dimensional echocardiograms received either
placebo (239 patients) or L-Carnitine (233 patients) within 24
h of onset of chest pain. Placebo or L-Carnitine was given at
a dose of 9 g/day intravenously for the first 5 days and then
6 g/day orally for the next 12 months. Left ventricular
volumes and ejection fraction were evaluated on admission, at
discharge from hospital and at 3, 6 and 12 months after acute
myocardial infarction.
RESULTS. A significant attenuation of left ventricular
dilation in the first year after acute myocardial infarction
was observed in patients treated with L-Carnitine compared
with those receiving placebo. The percent increase in both
end-diastolic and end-systolic volumes from admission to 3-,
6- and 12-month evaluation was significantly reduced in the
L-Carnitine group. No significant differences were observed in
left ventricular ejection fraction changes over time in the
two groups. Although not designed to demonstrate differences
in clinical end points, the combined incidence of death and
congestive heart failure after discharge was 14 (6%) in the
L-Carnitine treatment group versus 23 (9.6%) in the placebo
group (p = NS). Incidence of ischemic events during follow-up
was similar in the two groups of patients.
CONCLUSIONS. L-Carnitine treatment initiated early after
acute myocardial infarction and continued for 12 months can
attenuate left ventricular dilation during the first year
after an acute myocardial infarction, resulting in smaller
left ventricular volumes at 3, 6 and 12 months after the
emergent event.
The myocardial distribution and plasma
concentration of Carnitine in patients with mitral valve
disease.
Nakagawa T, Sunamori M, Suzuki A
Department of Thoracic-Cardiovascular Surgery, Tokyo Medical
University, School of Medicine, Japan.
Surg Today 1994;24(4):313-7
The myocardial distribution and concentration of Carnitine
and its fractions was studied in 11 patients with mitral valve
disease not associated with congestive heart failure (CHF).
The plasma concentration of Carnitine was found to be
identical to the normal values documented in the literature.
The left ventricular papillary muscle had the highest
concentrations of total, short-acyl, long-acyl, and free
Carnitine, being significantly higher than those of the right
ventricle, while the right atrial appendage had the lowest
values of all fractions of Carnitine. The proportion of
long-acyl Carnitine to total Carnitine was significantly
greater in the left ventricle than in either the right atrium
or the atrial septum, and other Carnitine fractions were
identical in all cardiac chambers. Our results suggest that in
the compensated heart with mitral valve disease, Carnitine and
its fractions are greatest in the left ventricle in the
muscles of all cardiac chambers, and that long-acyl Carnitine
is most likely to be linked to the cardiac muscle demanding a
higher cardiac performance.
Myocardial Carnitine metabolism in congestive heart
failure induced by incessant tachycardia.
Pierpont ME, Foker JE, Pierpont GL
Department of Pediatrics, University of Minnesota, School of
Medicine, Minneapolis.
Basic Res Cardiol 1993 Jul-Aug;88(4):362-70
Persistent tachycardia induces congestive heart failure
(CHF), but the mechanism(s) of progressive ventricular
dysfunction is (are) unclear. This study was designed to
define possible metabolic causes of myocardial dysfunction in
rapid ventricular pacing induced CHF. Twelve adult mongrel
dogs were paced to 250 beats/min for 19 days. Plasma
Carnitine, norepinephrine and renin were measured at 0, 1, 2,
and 3 weeks. Myocardial high energy phosphates, Carnitine,
glycogen, glucose, non-collagenous protein and collagen were
measured at 19 days. Cardiac output, arterial pressure and
pulmonary wedge pressure, measured at baseline and with CHF,
showed a decrease in cardiac output and increase in pulmonary
wedge pressure. Neurohumoral activation was evident by
progressively increasing plasma norepinephrine and renin
activity and depletion of myocardial norepinephrine. Plasma
free Carnitine rose significantly from 12.6 +/- 2.0 control to
28.3 +/- 3.8 nmol/ml at 19 days (p < 0.001), whereas
myocardial total Carnitine was lower in paced than in control
dogs (6.0 +/- 1.9 vs. 14.1 +/- 3.5 nmol/mg non-collagenous
protein, p < 0.001). Myocardial ATP ATP and ADP were
unchanged, while AMP decreased 22%, and creatine phosphate
decreased 30% compared to control animals. Myocardial glucose
was normal but glycogen was decreased 54% (p < 0.005). The
low myocardial Carnitine and elevated plasma Carnitine in
pacing induced CHF suggests altered Carnitine transport or
membrane integrity.
[The clinical and hemodynamic effects of
propionyl-L-Carnitine in the treatment of congestive heart
failure]
Pucciarelli G, Mastursi M, Latte S, Sacra C, Setaro A,
Lizzadro A, Nolfe G
Servizio di Cardiologia, USL n. 42, Ospedale Elena D'Aosta,
Napoli.
Clin Ter 1992 Nov;141(11):379-84
In order to evaluate the clinical and hemodynamic effects
of propionyl-L-Carnitine (PLC) a randomized, double-blind
study versus placebo was performed in 50 patients of both
sexes, between 48 and 69 years of age, affected by
mild-moderate congestive heart failure. All patients
participating in said study were on digitalis and diuretic
treatment. 25 of these belonged to the control group, while
the other 25 were treated with an oral dose of 1 g b.i.d of
propionyl-L-Carnitine. At the end of six months of treatment
maximum exercise time on the treadmill increased 11.1% after
90 days and 16.4% after 180 in the group treated with PLC.
From a hemodynamic standpoint, after 30, 90 and 180 days the
ejection fraction increased by 7.3%, 10.7% and 12.1%. At the
same time, moreover, the systemic vascular resistances were
reduced by 14.9%, 20% and 20.6%. In the patients treated with
placebo, however, the above-mentioned parameters showed no
significant variation. Finally, no unexpected events or toxic
effects were observed in any of the patients in either group.
As a consequence of these results it is possible to affirm
that propionyl-L-Carnitine, due to its clinical and
hemodynamic effects, represents a drug of notable therapeutic
interest in patients with congestive heart failure, in whom it
may be usefully combined with the usual pharmacological
therapy.
L-Carnitine treatment for congestive heart
failure--experimental and clinical study.
Kobayashi A, Masumura Y, Yamazaki N
Third Department of Internal Medicine, Hamamatsu University
School of Medicine, Japan
Jpn Circ J 1992 Jan;56(1):86-94
To evaluate the therapeutic efficacy of l-Carnitine in
heart failure, the myocardial Carnitine levels and the
therapeutic efficacy of l-Carnitine were studied in
cardiomyopathic BIO 14.6 hamsters and in patients with chronic
congestive heart failure and ischemic heart disease. BIO 14.6
hamsters and patients with heart failure were found to have
reduced myocardial free Carnitine levels (BIO 14.6 vs FI, 287
+/- 26.0 vs 384.8 +/83.8 nmol/g wet weight, p less than 0.05;
patients with heart failure vs without heart failure, 412 +/-
142 vs 769 +/- 267 nmol/g p less than 0.01). On the other
hand, long-chain acylCarnitine level was significantly higher
in the patients with heart failure (532 +/- 169 vs 317 +/- 72
nmol/g, p less than 0.01). Significant myocardial damage in
BIO 14.6 hamsters was prevented by the intraperitoneal
administration of l-Carnitine in the early stage of
cardiomyopathy. Similarly, oral administration of l-Carnitine
for 12 weeks significantly improved the exercise tolerance of
patients with effort angina. In 9 patients with chronic
congestive heart failure, 5 patients (55%) moved to a lower
NYHA class and the overall condition was improved in 6
patients (66%) after treatment with l-Carnitine. L-Carnitine
is capable of reversing the inhibition of adenine nucleotide
translocase and thus can restore the fatty acid oxidation
mechanism which constitutes the main energy source for the
myocardium. Therefore, these results indicate that l-Carnitine
is a useful therapeutic agent for the treatment of congestive
heart failure in combination with traditional pharmacological
therapy.
The therapeutic potential of Carnitine in
cardiovascular disorders.
Pepine CJ
Division of Cardiology, University of Florida,
Gainesville.
Clin Ther 1991 Jan-Feb;13(1):2-21; discussion 1
The naturally occurring compound L-Carnitine plays an
essential role in fatty acid metabolism. It is only by
combining with Carnitine that the activated long-chain fatty
acyl coenzyme A esters in the cytosol are able to be
transported to the mitochondrial matrix where beta-oxidation
occurs. Carnitine also functions in the removal of compounds
that are toxic to metabolic pathways. Clinical evidence
indicates that Carnitine may have a role in the management of
a number of cardiovascular disorders. Supplemental
administration of Carnitine has been shown to reverse
cardiomyopathy in patients with systemic Carnitine deficiency.
Experimental evidence obtained in laboratory animals and the
initial clinical experience in man indicate that Carnitine may
also have potential in the management of both chronic and
acute ischemic syndromes. Peripheral vascular disease,
congestive heart failure, cardiac arrhythmias, and
anthracycline-induced cardiotoxicity are other cardiovascular
conditions that may benefit from Carnitine administration,
although at this time data on the use of Carnitine for these
indications are very preliminary. (53 Refs.)
[Dilated cardiomyopathy due to primary Carnitine
deficiency]
Squarcia U, Agnetti A, Caffarra A, Cavalli C, Marbini A
Pediatr Med Chir 1986 Mar-Apr;8(2):157-61
A case of a 3 and a half years old girl with severe
congestive heart failure, and typical picture of dilated
cardiomyopathy is presented. The serum level of Carnitine
(17.2 micromoles/l, versus 44.1 +/- 12.2 micromoles/l, normal
value for age) and the histologic and biochemical evaluation
of quadriceps muscle tissue confirmed the diagnosis of primary
deficit of Carnitine. L-Carnitine (2 gr. three times a day
p.o.) was added to anti-congestive therapy. After 8 weeks of
therapy, the general and cardiocirculatory conditions are much
improved. The physiopathology of dilated cardiomyopathy due to
deficit of Carnitine are discussed. An early diagnosis, and an
early substitutive therapy with L-Carnitine dramatically
improve the outcome of the disease.
Characterization of inwardly rectifying K+ channel
in human cardiac myocytes. Alterations in channel behavior in
myocytes isolated from patients with idiopathic dilated
cardiomyopathy.
Koumi S, Backer CL, Arentzen CE
Department of Medicine, Northwestern University School of
Medicine, Chicago, Ill., USA.
Circulation 1995 Jul 15;92(2):164-74
BACKGROUND: Little is known about the characteristics of
the inwardly rectifying K+ channel (IK1) and the influence of
preexisting heart disease on the channel properties in the
human heart.
METHODS AND RESULTS: We studied the characteristics of
cardiac IK1 in freshly isolated adult human atrial and
ventricular myocytes by using the patch-clamp technique.
Specimens were obtained from the atria and ventricles of 48
patients undergoing cardiac surgery or transplantation and
from four explanted donor hearts. The action potential in
ventricular myocytes exhibited a longer duration (391.4
+/-30.2 milliseconds at 90% repolarization, n = 10) than in
atrium (289.4 +/- 23.0 milliseconds, n = 18, P < .001) and
had a fast late repolarization phase (phase 3). The final
phase of repolarization in ventricle was frequency
independent. Whole-cell IK1 in ventricle exhibited greater
slope conductance (84.0 +/- 7.9 nS at the reversal potential,
EK; n = 27) than in atrium (9.7 +/-1.2 nS at EK; n = 8, P <
.001). The steady-state current-voltage (I-V) relation in
ventricular IK1 demonstrated inward rectification with a
region of negative slope. This negative slope region was not
prominent in atrial IK1. The macroscopic currents were blocked
by Ba2+ and Cs+. The channel characteristics in ventricular
myocytes from patients with congestive heart failure after
idiopathic dilated cardiomyopathy (DCM) exhibited distinct
properties compared with those from patients with ischemic
cardiomyopathy (ICM). The action potential in ventricular
myocytes from patients with DCM had a longer duration (490.8
+/- 24.5 milliseconds, n = 11) compared with that for ICM
(420.6 +/- 29.6 milliseconds, n = 11, P < .01) and had a
slow repolarization phase (phase 3) with a low resting
membrane potential. The whole-cell current slope conductance
for DCM was smaller (41.2 +/- 9.0 nS at EK, n = 7) than that
for ICM (80.7 +/- 17.0 nS, n = 6, P < .05). In
single-channel recordings from cell-attached patches,
ventricular IK1 channels had characteristics similar to those
of atrial IK1; channel openings occurred in long-lasting
bursts with similar conductance and gating kinetics. In
contrast, the percent of patches in which IK1 channels were
found was 34.7% (25 of 72) of patches in atrium and 88.6% (31
of 35) of patches in ventricle. Single IK1 channel activity
for DCM exhibited frequent long-lasting bursts separated by
brief interburst intervals at every holding voltage with the
open probability displaying little voltage sensitivity
(approximately 0.6). Channel activity was observed in 56.2%
(18 of 32) of patches for DCM and 77.4% (24 of 31) of patches
for ICM. Similar results were obtained from atrial IK1
channels for DCM. In addition, channel characteristics were
not significantly different between ICM and explanted donor
hearts (donors). IK1 channels in cat and guinea pig had
characteristics virtually similar to those of humans, with the
exception of lower open probability than that in humans.
CONCLUSIONS: These results suggest that the
electrophysiological characteristics of human atrial and
ventricular IK1 channels were similar to those of other
mammalian hearts, with the possible exception that the channel
open probability in humans may be higher, that the whole-cell
IK1 density is higher in human ventricle than in atrium, and
that IK1 channels in patients with DCM exhibited
electrophysiological properties distinct from IK1 channels
found in patients with ICM and in donors.
Impaired forearm vasodilation to hyperosmolal
stimuli in patients with congestive heart failure secondary to
idiopathic dilated cardiomyopathy or to ischemic
cardiomyopathy.
Bank AJ, Rector TS, Burke MN, Tschumperlin LK, Kubo
SH
Cardiovascular Division, University of Minnesota Medical
School, Minneapolis 55455.
Am J Cardiol 1992 Nov 15;70(15):1315-9
Patients with congestive heart failure (CHF) have impaired
peripheral vasodilation during exercise. Hyperosmolality is
one local stimulus that produces vasodilation during exercise
in normal subjects. This study addressed the hypothesis that
vasodilation to hyperosmolal stimuli is impaired in patients
with CHF. Forearm blood flow responses to intrabrachial artery
infusions of isoosmolar (280 mosm/kg) and hyperosmolal (480
and 660 mosm/kg) solutions of saline and glucose were compared
in 9 patients with CHF and 13 normal subjects. Forearm blood
flow was measured by strain gauge plethysmography. In the
normal subjects, hyperosmolal infusions of 480 and 660 mosm/kg
increased forearm blood flow by 3.12 +/0.40 and 6.80 +/- 0.67
ml/min/100 ml forearm volume, respectively (both p< 0.001
compared with isoosmolal infusions). In contrast, in the
patients with CHF, these infusions increased forearm blood
flow by 2.19 +/- 0.44 and 4.06 +/- 0.92 ml/min/100 ml forearm
volume (p < 0.05 normal vs CHF). The impaired forearm blood
flow responses in heart failure occurred despite significantly
greater (p < 0.05, normal vs CHF) increases in venous
osmolality (17.3 +/- 6.5 vs 9.6 +/- 1.3 mosm/kg for the 660
mosm/kg infusion). There were no differences between groups in
forearm venous hematocrit, calcium, and sodium or potassium
changes during hyperosmolal infusions. It is concluded that
peripheral vasodilation to hyperosmolal stimuli is impaired in
patients with CHF.
Usefulness of coenzyme Q10 in clinical cardiology:
a long-term study.
Langsjoen H, Langsjoen P, Langsjoen P, Willis R, Folkers
K
University of Texas Medical Branch, Galveston 77551,
USA.
Mol Aspects Med 1994;15 Suppl:s165-75
Over an eight year period (1985-1993), we treated 424
patients with various forms of cardiovascular disease by
adding coenzyme Q10 (CoQ10) to their medical regimens. Doses
of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242
mg). Treatment was primarily guided by the patient's clinical
response. In many instances, CoQ10 levels were employed with
the aim of producing a whole blood level greater than or equal
to 2.10 micrograms/ml (average 2.92 micrograms/ml, n = 297).
Patients were followed for an average of 17.8 months, with a
total accumulation of 632 patient years. Eleven patients were
omitted from this study: 10 due to non-compliance and one who
experienced nausea. Eighteen deaths occurred during the study
period with 10 attributable to cardiac causes. Patients were
divided into six diagnostic categories: ischemic
cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary
diastolic dysfunction (PDD), hypertension (HTN), mitral valve
prolapse (MVP) and valvular heart disease (VHD). For the
entire group and for each diagnostic category, we evaluated
clinical response according to the New York Heart Association
(NYHA) functional scale, and found significant improvement. Of
424 patients, 58 per cent improved by one NYHA class, 28% by
two classes and 1.2% by three classes. A statistically
significant improvement in myocardial function was documented
using the following echocardiographic parameters: left
ventricular wall thickness, mitral valve inflow slope and
fractional shortening. Before treatment with CoQ10, most
patients were taking from one to five cardiac medications.
During this study, overall medication requirements dropped
considerably: 43% stopped between one and three drugs. Only 6%
of the patients required the addition of one drug. No apparent
side effects from CoQ10 treatment were noted other than a
single case of transient nausea. In conclusion, CoQ10 is a
safe and effective adjunctive treatment for a broad range of
cardiovascular diseases, producing gratifying clinical
responses while easing the medical and financial burden of
multidrug therapy.
Bioenergetics in clinical medicine. Studies on
coenzyme Q10 and essential hypertension.
Yamagami T, Shibata N, Folkers K
Res Commun Chem Pathol Pharmacol 1975
Jun;11(2):273-88
The specific activities (S.A.) of the succinate
dehydrogenase-coenzyme Q10 (CoQ10) reductase of a control
group of 65 Japanese adults and 59 patients having essential
hypertension were determined. The mean S.A. of the
hypertensive group was significantly lower (p less than 0.001)
and the mean % deficiency of enzyme activity was significantly
higher (p less than 0.001) than the values for the control
group. These data on Japanese in Osaka agree with data on
Americans in Dallas. Some patients showed no CoQ10-deficiency,
and others showed definite deficiencies. Emphasizing the
CoQ10-enzyme for patient selection, CoQ10 was administered to
hypertensive patients. Four individuals showed significant but
partial reductions of blood pressure. Monitoring the
CoQ10-enzyme before, during, and after administration of CoQ10
indicated responses. The maintenance of high blood pressure
could be primarily due to contraction of the arterial wall.
Contraction or relaxation of an arterial wall is dependent
upon bioenergetics, which also provide the energy for
biosynthesis of angiotensin II, renin, aldosterone, and the
energy for sodium and potassium transport. A clinical benefit
from administration of CoQ10 to patients with essential
hypertension could be based upon correcting a deficiency in
bioenergetics, and point to possible combination treatments
with a form of CoQ and anti-hypertensive drugs.
Can antioxidants prevent ischemic heart
disease?
Maxwell SR
Queen Elizabeth Hospital, Edgbaston, Birmingham, U.K.
J Clin Pharm Ther 1993 Apr;18(2):85-95
Ischemic heart disease remains a major cause of mortality
in developed countries. A number of important risk factors for
the development of coronary atherosclerosis have been
identified including hypertension, hypercholesterolaemia,
insulin resistance and smoking. However, these factors can
only partly explain variations in the incidence of ischaemic
heart disease either between populations or within populations
over time. In addition, population interventions based upon
these factors have had little impact in the primary prevention
of heart disease. Recent evidence suggests that one of the
important mechanisms predisposing to the development of
atherosclerosis is oxidation of the cholesterol-rich
low-density lipoprotein particle. This modification
accelerates its uptake into macrophages, thereby leading to
the formation of the cholesterol-laden 'foam cell'. In vitro,
low-density lipoprotein oxidation can be prevented by
naturally occurring antioxidants such as vitamin C, vitamin E
and beta-carotene. This article explores the evidence that
these dietary anti-oxidants may influence the rate of
progression of coronary atherosclerosis in vivo and discusses
the need for formal clinical trials of antioxidant
therapy.
Antioxidant therapy in the aging process.
Deucher GP
Clinica Guilherme Paulo Deucher, Sao Paulo, Brazil.
EXS 1992;62:428-37
A total of 1,265 patients with age-related diseases such as
diabetes, arthritis, vascular disease and hypertension as well
as 1,100 persons in diminished health without apparent
disease, were treated with the metal chelator EDTA and
antioxidants such as vitamin C, E, beta-carotene, selenium,
zinc and chromium. Good results were observed in the majority
of patients. This is encouraging for the initiation of
controlled clinical trials.
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