Alternative Therapies for Chronic Stable Angina in Patients Refractory to Medical Therapy Who Are Not Candidates for Percutaneous Intervention or Revascularization 163 A. Spinal Cord Stimulation 163 ...B. Enhanced External Counterpulsation 164 C. Laser TMR 164 V. Asymptomatic Patients With Known or Suspected Coronary Artery Disease 164 A. Treatment of Risk Factors 166 B. Revascularization 166 References 167 Introduction The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines regularly reviews existing guidelines to determine when an update or a full revision is needed. Risk Factor Defining Level Abdominal obesity Waist circumference Men Greater than 103 cm (40 in) Women Greater than 88 cm (35 in) Triglycerides Greater than 150 mg/dL HDL cholesterol Men Less than 40 mg/dL Women Less than 50 mg/dL Blood pressure Greater than or equal to 130/85 mm Hg Fasting serum glucose Greater than or equal to 110 mg/dL Table Characteristics Used to Define Metabolic Syndrome
The effects of extracellular matrix proteins and mechanical strain on the mitogenic activity of angiotensins I and II (AI and AII) were examined in cultured rat vascular smooth muscle (VSM) cells. ...VSM cells on various extracellular matrices were exposed to AII (1 microM) for 48 h. On plastic, AII induced only a 1.6-fold increase in 3Hthymidine incorporation, but on fibronectin- or type I collagen-coated plastic, the response to AII was enhanced from two- to fourfold. On a type I collagen-coated silicone elastomer, to which mechanical strain was applied, 3Hthymidine incorporation dramatically increased to a maximum of 53-fold. Dup 753 (10(-5) M) blocked the AII-induced increase in DNA synthesis. AI also increased DNA synthesis in VSM cells, and this response was also enhanced by mechanical strain. Mitogenic activity of AI was blocked by ramiprilat (10(-5) M), indicating that its mitogenic activity was via conversion to AII. The synergy between AII and strain was completely eliminated by neutralizing antibodies to PDGF AB (3 micrograms/ml). Furthermore, the mitogenic effect of AII in unstrained cells was also synergistic with submaximal concentrations of PDGF AB (1 ng/ml). Thus, the synergy between AII and mechanical strain probably results from synergism between AII and PDGF secreted in response to strain.
Levosimendan is a calcium-sensitizing agent and an inodilator under current investigation in the treatment of decompensated heart failure. The effects of intravenous levosimendan on the human ...coronary vasculature, together with myocardial wall stress and oxygen uptake, have not been adequately studied.
Ten adult patients underwent right- and left-heart catheterization. Baseline coronary blood flow was determined with quantitative coronary angiography and an intracoronary Doppler-tipped guidewire. Myocardial oxygen uptake was measured with a coronary sinus catheter. Echocardiography was performed before and 30 minutes after an intravenous infusion of levosimendan (24-microg/kg bolus over 10 minutes) was begun. Pulmonary capillary wedge decreased 37% (P=0.009), cardiac output increased 9% (P=0.04), and systemic vascular resistance decreased 18% (P<0.001). Left ventricular ejection fraction increased 20% (P=0.009), and meridional systolic wall stress decreased 48% (P=0.009). Coronary artery diameter increased 10% at 15 minutes (P=0.001) and 11% at 30 minutes (P=0.01). Coronary artery velocity increased 10% over baseline (P=0.04). Coronary blood flow increased 45% (P=0.02), whereas coronary resistance decreased 36% at 30 minutes (P=0.03). Myocardial oxygen extraction decreased 9% at 30 minutes (P=0.04).
Levosimendan given intravenously exerts vasodilator effects on human coronary conductance and resistance arteries. Despite a decrease in coronary perfusion pressure, coronary blood flow is increased. A reduction in coronary vascular resistance and a decrease in coronary venous oxygen content indicate primary coronary vasodilation by levosimendan. Improved left ventricular systolic function and decreased myocardial oxygen extraction suggest improved myocardial efficiency.
Cyclosporin A is reported to impair endothelium-mediated vasorelaxation and induce endothelin release in some noncoronary vascular beds. We wished to determine whether acute cyclosporine ...administration induces endothelial dysfunction in coronary conductance or resistance arteries.
We examined the effect of intracoronary acetylcholine, N omega-nitro-L-arginine methyl ester (L-NAME), L-arginine, nitroglycerin, and adenosine before and after acute cyclosporine administration (3 mg/kg IV over 30 minutes) in anesthetized dogs. Flow velocity was measured with a 0.014-in Doppler wire to assess resistance vessel responses, and epicardial coronary lumen area was simultaneously measured with a 4.3F, 30-MHz imaging catheter inserted over the Doppler wire. In 6 dogs, acetylcholine-induced increase in flow velocity was attenuated by cyclosporine in vehicle (137% to 55% at 10(-5) mol/L, P < .001), as was acetylcholine-induced epicardial vasodilation (14.1% to 6.7% at 10(-5) mol/L, P < .001). Vasodilation in response to intracoronary nitroglycerin (200 micrograms) and adenosine (6 mg) were unchanged by cyclosporine. Epicardial vasoconstriction with L-NAME (10(-4) mol/L) was reduced by cyclosporine (Pre, 7.4 +/- 0.9%; Post, 2.6 +/- 1.2%; P = .04), but L-arginine (10(-4) mol/L) had no effect after cyclosporine. In another 5 dogs, pure cyclosporine impaired acetylcholine-induced vasodilatation to the same degree as cyclosporine in vehicle (Cremophor); vehicle infusion did not impair endothelial function. In 5 more dogs, cyclosporine did not increase either arterial or coronary sinus concentrations of endothelin-1.
The present study shows that cyclosporine acutely impairs release of endothelium-derived relaxing factor in canine conductance and resistance coronary arteries and provides evidence for decreased epicardial nitric oxide release after cyclosporine. The potential contribution of acute cyclosporine-induced coronary endothelial dysfunction to posttransplant vasculopathy needs further study.
Vincristine attenuates doxorubicin cardiotoxicity Chatterjee, Kanu; Zhang, Jianqing; Tao, Rong ...
Biochemical and biophysical research communications,
09/2008, Letnik:
373, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Our aim was to test the hypothesis that the vinca alkaloid vincristine could prevent doxorubicin-induced cardiomyocyte death and to identify the mechanisms involved. Adult mouse cardiac myocytes were ...incubated for 24h with doxorubicin, with and without concurrent vincristine. Trypan blue exclusion showed that 50–60% of myocytes treated with doxorubicin alone survived. Concurrent vincristine treatment increased survival to ⩾85%. Treatment with doxorubicin+vincristine activated the prosurvival signal Akt and diminished cytochrome C release. The PI3K/Akt inhibitor LY294002 and the MEK/ERK inhibitor PD98059 augmented doxorubicin cardiotoxicity and attenuated salvage during concurrent vincristine treatment, indicating that the mechanism of vincristine cardioprotection involves activation of specific survival signals. Vincristine retarded the onset of apoptosis in association with a delay in poly(ADP) ribose polymerase activation. Vincristine also exhibited greater protection than the antioxidant MPG. These novel findings may have clinical implications for the prevention of doxorubicin cardiomyopathy.
Systolic heart failure is characterized by ventricular dilation and reduced ejection fraction, and this syndrome may be either chronic or acute. Left ventricular remodeling is the principal cause of ...progression of systolic heart failure. Acute heart failure resulting from cardiomyopathy has similar functional and morphologic abnormalities. This review discusses remodeling, initial therapy based on neurohormonal modulation, and treatment of decompensated and refractory heart failure. Diagnosis, prognosis, and management of acute myocarditis are also discussed.
Left ventricular systolic dysfunction is associated with neurohormonal activation which contributes to progressive ventricular remodeling and worsening clinical heart failure. ...Renin-angiotensin-aldosterone and sympathetic nervous systems are activated, not only in patients with clinically overt heart failure, but also in patients with asymptomatic or minimally symptomatic left ventricular systolic dysfunction. Activation of the angiotensin and adrenergic systems produces deleterious effects on systemic and coronary hemodynamics, promotes myocyte hypertrophy and fibroblast growth, and myocyte necrosis and apoptosis. Thus, therapy of heart failure should consist of pharmacologic agents not only to relieve symptoms but also to prevent and attenuate ventricular remodeling and progressive heart failure, thereby improving prognosis. In patients who are symptomatic, ACE inhibitors along with digitalis and diuretics as initial therapy (triple therapy) have the greater potential to improve exercise tolerance and decrease the incidence of treatment failure compared with diuretics alone or a combination of diuretics and digitalis. Diuretics alone should not be considered for long-term therapy as plasma renin activity, angiotensin II, aldosterone, norepinephrine and vasopressin levels may increase. ACE inhibitors decrease mortality in patients with heart failure resulting from left ventricular systolic dysfunction. The results of presently available studies indicate that angiotensin II receptor blockers (ARBs) do not provide any advantage over ACE inhibitors regarding survival benefit but may be better tolerated. Long-term adrenergic inhibition with the use of ss-adrenoceptor antagonists added to ACE inhibitors is associated with attenuation of ventricular remodeling, improvement in ventricular function and clinical class and survival of patients with symptomatic systolic left ventricular failure. Thus, initial pharmacotherapy for systolic heart failure should consist of: maximal tolerated dosages of ACE inhibitors;ARBs if ACE inhibitors are not tolerated because of intractable cough or angioedema;adequate dosages of hydralazine and isosorbide dinitrate if ACE inhibitors or ARBs are not tolerated; relatively low dosages of digoxin (serum concentrations of < or = 1.0 ng/dl) if not contraindicated; and diuretics to relieve congestive symptoms. Addition of spironolactone to ACE inhibitors can result in a significant reduction in the risk of sudden death in patients with symptomatic severe heart failure. Myocardial infarction resulting from ischemic heart disease is the most common cause of systolic left ventricular failure and the therapeutic modalities with potential to reduce the risks of myocardial infraction, such as risk factor modification, adequate control of diabetes and hypertension, antiplatelet agents and lipid-lowering agents, should also be included in the initial therapy.
Although angiotensin converting enzyme (ACE) inhibitors have been reported to increase coronary blood flow, the effect of selective angiotensin II (AT1)-receptor antagonism on the coronary ...circulation has not been defined.
We examined the effects of the AT1-receptor antagonist Losartan (DuP 753, 0.2-3.2 mg/kg) on coronary arteries in vivo in 11 dogs, using a combination of intravascular two-dimensional and Doppler ultrasound. In six dogs, a 30-MHz, 4.3F ultrasound imaging catheter was placed in the midsegment of the circumflex coronary artery to measure cross-sectional area (CSA), and a 0.018-in. Doppler wire was placed alongside to measure coronary flow velocity. At peak effect (1.6 mg/kg), Losartan increased mean coronary CSA from 7.9 +/- 0.5 to 9.5 +/- 0.8 mm2 and average peak velocity (APV) from 32 +/- 10 to 56 +/- 18 cm/sec, resulting in an increase in coronary blood flow from 74 +/- 19 to 151 +/- 36 mL/min. The maximal effect of the ACE inhibitor enalaprilat (5 mg) was an increase in CSA from 7.7 +/- 0.7 to 8.4 +/- 0.8 mm2 and an increase in APV from 36 +/- 10 to 53 +/- 20 cm/sec, with an increase in coronary blood flow from 82 +/- 25 to 122 +/- 41 mL/min. Relative to maximal hyperemia with adenosine (6 mg i.c.), the magnitude of flow increase from baseline was 0.37 with the AT1-receptor antagonist and 0.19 with the ACE inhibitor (p < 0.05). These effects were seen without changes in heart rate or systemic arterial pressure. In an additional five dogs, the ultrasound imaging catheter was introduced directly over a 0.014-in. Doppler wire, and the effects of indomethacin, propranolol, and N omega-nitro-L-arginine methylester (L-NAME) on the vasodilator effect of Losartan (1.6 mg/kg) were examined. Indomethacin and propranolol had no effect on Losartan-induced vasodilation, suggesting that it was not mediated via prostaglandins or beta-adrenoceptors. However, Losartan-induced epicardial vasodilation was partially inhibited by L-NAME, suggesting an action partly dependent on endothelial release of nitric oxide.
Thus, these acute studies in anesthetized dogs suggest that inhibition of AT1-receptors in the coronary circulation results in vasodilator responses greater in magnitude than ACE inhibition and partly endothelium dependent. The exact role for AT1-receptors in human coronary physiology and pathology remains to be defined.
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