Showing papers in "Cardiovascular Drugs and Therapy in 2001"

The EPHESUS trial: Eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction

Abstract: The importance of aldosterone in the pathophysiology of chronic heart failure (HF) has been established in previous studies [1–4] and is emphasized by the findings of the RALES trial [5]. In this study, aldosterone blockade with spironolactone resulted in a 30% reduction in total mortality and a 35% reduction in hospitalizations for HF in patients with pre-existing chronic severe HF. Patients in the RALES trial also received standard therapy including an ACE inhibitor (if tolerated), a loop diuretic, and digoxin. While aldosterone receptor blockade has been proven beneficial in severe chronic HF due to systolic left ventricular (LV) dysfunction, its effects in patients with acute myocardial infarction (AMI) complicated by HF due to systolic left ventricular dysfunction are unknown. The pathophysiology of HF complicating AMI is complex. Factors such as the acute release of catecholamines, activation of the renin angiotensin aldosterone system, degree of ventricular remodeling, myocardial scar formation, extent of coronary artery disease, and residual ischemia may differ both quantitatively and qualitatively in patients with acute infarction compared to patients with chronic HF. Additionally, the extent of activation of cytokines, fibrinolytic balance, and activity of clotting factors may differ. Eplerenone was chosen for this study because of its demonstrated efficacy in an experimental model of AMI [6]. In clinical trials, eplerenone demonstrated efficacy similar to spironolactone in blocking aldosterone receptors, lowering blood pressure, and moderating hormonal and neurohormonal markers of HF [7,8]. However, eplerenone has significantly less affinity for androgen and progesterone receptors and should therefore be associated with a lower incidence of gynecomastia, breast pain and impotency in males, and diminished libido and menstrual irregularities in females [9–11]. While older patients suffering from refractory HF may tolerate these androgenic and progestational side effects, they may preclude widespread use of a nonspecific aldosterone antagonist in younger patients or in patients with less severe cardiac compromise. Since eplerenone is at least 100 times more specific in its affinity for aldosterone receptors than is spironolactone, if the hypothesis being tested in the EPHESUS trial proves correct, eplerenone has the potential to be used in a broad population to prevent progressive left ventricular remodeling, ventricular fibrosis, malignant arrhythmias, non-fatal AMI, and sudden cardiac death. We hypothesize that selective aldosterone receptor blockade with eplerenone will have a beneficial effect on survival and morbidity in patients with AMI complicated by HF due to systolic left ventricular dysfunction. This paper describes the background, design, and organization of a trial to test this hypothesis—the EPHESUS trial (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study).

Safety of HMG-CoA reductase inhibitors: focus on atorvastatin.

Abstract: Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease. Statins are in general well tolerated. Withdrawal rates related to adverse events are low (≤3%). The most common adverse events are mild gastrointestinal symptoms. Elevated serum transaminase levels occur infrequently (≤1.5%). These are generally asymptomatic, reversible and rarely require drug withdrawal. Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk. Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g. erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme. The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions. Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins.

Effects of melatonin on ischemia and reperfusion injury of the rat heart.

Abstract: Effects of melatonin on various manifestations of ischemia/reperfusion injury of the isolated perfused rat heart were examined Ischemia- and reperfusion-induced ventricular arrhythmias were studied under constant flow in hearts subjected to 10, 15 or 25 min of regional ischemia (induced by LAD coronary artery occlusion) and 10-min reperfusion Melatonin was added to the perfusion medium 5 min before ischemia at concentrations of 10 μmol/l or 10 nmol/l and was present throughout the experiment Recovery of the contractile function was evaluated under constant perfusion pressure after 20-min global ischemia followed by 40-min reperfusion Hearts were treated with melatonin at a high concentration (10 μmol/l) either 5 min before ischemia only (M1) or 5 min before ischemia and during reperfusion (M2) or only during reperfusion (M3) At the high concentration, melatonin significantly reduced the incidence of reperfusion-induced ventricular fibrillation and decreased arrhythmia score (10% and 22 ± 03, respectively) as compared with the corresponding untreated group (62% and 41 ± 03, respectively); the low concentration had no effect This substance did not affect the incidence and severity of ischemic arrhythmias Melatonin (M2, M3) significantly improved the recovery of the contractile function as compared with the untreated group; this protection did not appear if melatonin was absent in the medium during reperfusion (M1) Our results show that melatonin, in accordance with its potent antioxidant properties, effectively protects the rat heart against injury associated with reperfusion It appears unlikely that melatonin is cardioprotective at physiological concentrations

Phospholamban: a promising therapeutic target in heart failure?

Abstract: Dilated cardiomyopathy and end-stage heart failure result in characteristic functional, biochemical and molecular alterations Multiple defects in cardiac excitation-contraction coupling have been suggested to underlie disturbed myocardial function and progressive remodeling Ca2+ uptake and release by the sarcoplasmic reticulum (SR) have been shown to be altered in various animal models and human conditions This review will focus on SR Ca2+ ATPase and its regulatory protein, phospholamban, as potential therapeutic targets We summarize structural and genetic approaches, which have helped to elucidate the physiological role of phospholamban as a principal regulator of cardiac contractility and beta-adrenergic stimulation in the heart These findings are extended to the clinical arena, indicating a phospholamban/SR Ca2+ ATPase mismatch in human heart failure Evidence is then provided, using genetically engineered mouse models, that SR dysfunction may play a key role in the onset and progression of heart failure Phospholamban deficiency may prevent such left ventricular dysfunction and its progression to heart failure in some of the animal models with dilated cardiomyopathy Based on these findings, we discuss the question of whether and how interfering with the phospholamban/SR Ca2+ ATPase interaction may be a promising therapeutic approach for heart failure

Mechanism of action of Ca2+ sensitizers--update 2001

Abstract: Ca2+ sensitizers act on the central mechanism (Ca2+ binding affinity of troponin C) and/or downstream mechanisms (thin filament regulation of actin and direct action on crossbridge cycling) of cardiac E–C coupling. Ca2+ sensitizers have mechanistic and energetic advantages over the agents that act through the upstream mechanism (intracellular Ca2+ mobilization). Ca2+ sensitizers and the agents that act through cyclic AMP-mediated signaling process have been postulated to belong to different classes, however, recent experimental findings revealed that certain Ca2+ sensitizers, such as levosimendan, OR 1896 and UD-CG 212 Cl, require cyclic AMP-mediated signaling for induction of the Ca2+ sensitizing effect. No clinically available agents act primarily via Ca2+ sensitization, but the positive inotropic effect of pimobendan and levosimendan is partly due to an increase in myofilament Ca2+ sensitivity. These agents are the hybrid of Ca2+ sensitizer and PDE III inhibitor. The extent of contribution of Ca2+ sensitizing effect of these agents to the clinical effectiveness to improve the hemodynamics in patients with heart failure is uncertain. Nevertheless pieces of evidence have been accumulating that these agents with Ca2+ sensitizing effect are clinically more effective than the agents that act purely via the upstream mechanism.

Apoptosis in cardiac disease - What is it - How does it occur

Abstract: This review will present a summary of a description of apoptotic pathways in the heart, followed by ways to measure it and the experimental and clinical evidence for the role of apoptosis in cardiac disease. An evaluation of the effectiveness of pharmacological and other therapeutic interventions in the prevention of apoptosis in the context of cardiac disease will also be presented.

The EUROPA trial: design, baseline demography and status of the substudies.

Abstract: Background: Angiotensin-converting enzyme inhibitors do reduce both mortality and morbidity in patients with left ventricular dysfunction, recent myocardial infarction and hypertension. However, the long-term effects in patients with coronary artery disease have not been established. The EUROPA study is designed to assess the long-term (3–4 years) effects of perindopril on the reduction of cardiac events in patients with proven stable coronary artery disease but with no evidence of heart failure.

Pharmacotherapy of dyslipidemia.

Abstract: Reducing elevated levels of low-density-lipoprotein cholesterol (LDL-C) significantly reduces the incidence of coronary heart disease (CHD) events and mortality in hypercholesterolemic patients. CHD risk reduction is proportional to LDL-C reduction. Despite this knowledge, many physicians are not applying existing treatment guidelines to the extent required to achieve target LDL-C levels. Target LDL-C levels are not achievable for most patients without drug therapy. Based on their lipid-lowering abilities, safety, and tolerability profiles, the HMG-CoA reductase inhibitors (statins) are the first-line pharmacotherapeutic agents for hypercholesterolemia. The ability of statins to reduce CHD events and total mortality in primary- and secondary-prevention patients also supports this assertion. For combined dyslipidemia, statin monotherapy is a reasonable initial approach in patients with moderate hypertriglyceridemia because statins effectively lower both LDL-C and triglycerides. Fibrates or niacin are effective therapies for severe hypertriglyceridemia. Resins are moderately effective in isolated hypercholesterolemia, and are a useful alternative to statins in pregnant women or patients with liver disease. For severe hyperlipidemia that does not respond to single drug therapy, combination drug therapy may be required. This article reviews the various manifestations of dyslipidemia and assesses the most efficacious treatments.

The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN)--rationale and design.

Abstract: Inhibition or reversal of ventricular remodelling in heart failure patients is regarded as of prime importance in the treatment of heart failure and in determining long term outcome. Recent studies have demonstrated that the addition of carvedilol to Angiotensin Converting Enzyme (ACE) inhibitors and other routine heart failure therapy results in a valuable improvement in the clinical status and life expectancy of mild, moderate and severe heart failure patients. ACE inhibitors have become the cornerstone of heart failure therapy. Also, carvedilol in combination with standard therapy (including ACE inhibitors) has demonstrable beneficial effects on left ventricular remodelling. Each new treatment has to be added, this quickly leads to polypharmacy, which may not be necessary and even unwanted in the individual patient, as the pharmacological profile of carvedilol compares favourably to ACE inhibitors, this suggests that it could challenge ACE inhibitors as first-line treatment for heart failure. The CARMEN trial (Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN) was designed to compare the effects of carvedilol alone and of carvedilol plus an ACE inhibitor (enalapril) with the effect of an ACE inhibitor alone on different parameters of left ventricular remodelling as well as morbidity and mortality in patients with chronic mild heart failure, thereby allowing conclusions on whether combination therapy may be replaced by the multiple action adrenergic inhibitor carvedilol in the future.

The Brugada syndrome.

Abstract: In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram (ECG) displaying a pattern resembling right bundle branch block with ST segment elevation in leads V1 to V3 was described. The disease is genetically determined with an autosomal dominant pattern of transmission in 50% of the familial cases. Several different mutations have been identified affecting the structure and the function of the sodium channel gene SCN5A. These mutations result in loss of function of the sodium channel. The syndrome appears ubiquitous. The incidence of the disease is difficult to estimate worldwide, but it may cause 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos. In these countries, the disease represents the most frequent cause of natural death in young adults. It is estimated that 20 to 50% of sudden deaths in patients with a normal heart result from this syndrome. The disease has been linked to the sudden infant death syndrome and to the sudden unexpected death syndrome by showing that the electrocardiogram and mutations are the same as in Brugada syndrome. The diagnosis is easily made by means of the ECG when it is typical. There exist, however, patients with concealed and intermittent electrocardiographic forms that make the diagnosis difficult. The ECG can be modulated by changes in autonomic balance, body temperature, glucose level, and the administration of drugs like antiarrhythmics, but also neuroleptic and antimalaria drugs.

Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling.

Abstract: Enhanced platelet activity and platelet endothelial interaction are hallmarks of different vascular and metabolic diseases with subsequent thrombus formation. In atherosclerosis, coronary artery disease, congestive heart failure, nitrate tolerance, chronic inflammation, or diabetic states, platelet activation may in part be due to a stimulation of the renin-angiotensin-aldosteron system, which also contributes to enhanced oxidant stress in these conditions.

Effects of mibefradil, a T- and L-type calcium channel blocker, on cardiac remodeling in the UM-X7.1 cardiomyopathic hamster.

Abstract: Abnormalities of T-type calcium channel function reported to occur in the transition phase to heart failure in the hamster cardiomyopathy may contribute to progression of the disease. We tested the hypothesis that chronic exposure to mibefradil, a selective T-type calcium channel blocker, improves the deleterious cardiac remodeling observed in this condition. In the present study, 40 normal (N) and 40 UM-X7.1 cardiomyopathic hamsters (CMH), aged 180 days, were treated daily by gavage for 21 days with mibefradil (30 mg/Kg). Eight to 10 animals from each group were sacrificed at the end of the treatment period while the remainder were followed for an additional 30 days without treatment (washout period). Hearts were harvested, fixed with 10%-buffered paraformaldehyde and then cut in half down the middle. Several slices were dehydrated, embedded in paraffin and stained with Masson Trichrome. Wall thickness and dilatation index of the left ventricle were estimated by planimetry. Myocardial capillary density was also computed. The greater heart weight/body weight ratio seen in untreated CMH (7.7 +/- 0.4 vs 5.5 +/- 0.2 in N, p < 0.05) was improved with mibefradil. The dilatation index averaged 0.504 +/- 0.04 in N was increased in untreated CMH (0.566 +/- 0.03) and ameliorated in mibefradil-treated CMH. The 1-month washout period led to further deterioration of the dilatation index in untreated and mibefradil-treated CMH. Capillary density averaged 10,000 +/- 781 per mm2 in hearts from untreated N hamsters and 8,830 +/- 795 per mm2 in untreated CMH (p = NS). Chronic exposure to mibefradil resulted in a significant reduction of capillary density in both N and CMH hearts. Following the 1-month washout period, the change in myocardial capillary density associated with mibefradil was no longer detectable. In conclusion, chronic exposure to mibefradil, a T- and L-type calcium channel blocker, exerts opposite effects during the transition phase to heart failure in CMH, improving the deleterious left ventricular remodeling in UM-X7.1 hamsters and reducting myocardial capillary density independently of the disease process.

Short Term Effect of Atorvastatin and Vitamin E on Serum Levels of C3, a Sensitive Marker of the Risk of Myocardial Infarction in Men

Abstract: C3 complement is produced in response to macrophage activation and is a reliable marker of the risk of myocardial infarction in men. This study was designed to ascertain whether the treatment with atorvastatin, a powerful cholesterol lowering drug, and/or vitamin E, a natural antioxidant, may induce a short term decrease in serum C3 in subjects with persistently elevated levels. From an initial random sample of 1100 men aged 55–64 years, 140 subjects with 3 consecutive C3 measurements in the high tertile (>1.19 g/l) were selected. Those with total cholesterol <5.56 mmol/l were double blindly randomized in groups 1 (placebo, N = 28, G1) and 2 (vitamin E 600 IU/day, N = 30, G2). The subjects with total cholesterol values ≥5.56 mmol/l were randomized in groups 3 (placebo, N = 30, G3), 4 (atorvastatin 10 mg/day, N = 27, G4) and 5 (atorvastatin 10 mg/day + vitamin E 600 IU/day, N = 25, G5). After 3 months C3 levels were substantially unchanged in the first 4 groups, while in G5 a very significant decrement occurred: −0.070 g/l (5.2%); 95% CI 0.043–0.098; p < 0.0001. “Normal” levels of C3 (≤1.19 g/l) were reached by 28% of G5 subjects. In G2 and G5 vitamin E levels increased by 60 and 36%, while in G4 they decreased by 23% (p < 0.0001), paralleling cholesterol and triglyceride fall. In all groups a progressive decrease in HDL cholesterol occurred (−17%, p < 0.0001). In conclusion, treatment with atorvastatin plus vitamin E for three months can lower persistently elevated C3 levels.

Apoptosis in cardiovascular remodeling--effect of medication.

Abstract: In the last decade, apoptosis has emerged as a key determinant of target organ damage in cardiovascular diseases. The suggestion that increased cardiomyocyte apoptosis participates in the etiology of heart failure probably contributed to the negative view of the prevalence of apoptosis in the field of cardiovascular diseases. However, we and others have shown that up-regulation of apoptosis in certain cardiovascular cells may contribute to the beneficial action of antihypertensive drugs on target-organ structure. As an explanation for this apparent discrepancy, the same stimulus, e.g. angiotensin II, can induce apoptosis or stimulate cell growth in different cell types (e.g., cardiomyocytes and fibroblasts, respectively). Using the angiotensin pathway as a paradigm, this review proposes an integrative view of cell growth and cell death regulation in cardiovascular cells in order to illustrate how cell-specific responses to the same stimulus may in part explain the patterns of cell population dynamics during the development and treatment of target organ damage in hypertension.

Insulin in Combination with Vanadate Stimulates Glucose Transport in Isolated Cardiomyocytes from Obese Zucker Rats

Abstract: Insulin stimulates glucose uptake in muscle cells via activation of protein kinase B (PKB). The protein tyrosine phosphatase (PTP) inhibitor vanadate, is a known insulin mimetic agent but the mechanism whereby vanadate exerts its effect is not clearly understood. Vanadate also has beneficial effects in the diabetic myocardium. The aim of this study was to correlate insulin stimulation of glucose uptake and PKB activation with that induced by vanadate in adult ventricular myocytes from lean and obese Zucker fa/fa rats. In lean Zucker rats, 100 nM insulin and 5 mM vanadate stimulated myocardial 2-deoxy-D-[3H]glucose (2-DG) uptake from 27.17 ± 1.72 to 96.52 ± 10.87 and 43.86 ± 4.02 pmole/mg protein p/30 min respectively while a combination of insulin and vanadate could not improve the maximal response of insulin. In obese Zucker hearts, basal as well as insulin and vanadate stimulated glucose uptake were severely impaired (15.49 ± 1.44 vs 25.51 ± 3.11 and 20.11 ± 1.68 pmole/mg protein/30 min respectively). A combination of insulin and vanadate, resulted in a response significantly improved from the maximal response of insulin. This stimulation of 2-DG uptake was, in all instances, blocked by the PI 3-kinase inhibitors wortmannin and LY 294002. Insulin could not activate PKB, as measured by the Ser473 phosphorylated form of the enzyme, in the obese Zucker rats to the same extent as in lean controls. Similar to glucose uptake, activation of PKB by vanadate plus insulin was significantly more than that accomplished by insulin alone in obese rats. Both insulin and vanadate activation of PKB was prevented by wortmannin and LY 294002. Thus, the present study demonstrates that: (i) in cardiomyocytes from lean and obese Zucker rats, both insulin and vanadate stimulate glucose uptake and PKB activation through a PI-3-kinase sensitive pathway. (ii) In obese Zucker rats, neither insulin nor vanadate could induce glucose uptake or activation of PKB to the same extent as in lean controls. (iii) A combination of insulin with vanadate may be beneficial to increase glucose uptake in diabetic hearts, as this gives a better response than insulin alone.

CHF-1024, a DA2/alpha2 agonist, blunts norepinephrine excretion and cardiac fibrosis in pressure overload.

Abstract: We compared the effects of an ACE inhibitor, captopril, with those of a DA2-dopaminergic/α2-adrenergic receptor agonist (CHF-1024) on neuroendocrine activation and cardiac fibrosis in a model of pressure-overload hypertrophy. Interrenal aortic stenosis was performed in 89 rats, treated with CHF-1024 (0.33, 2 or 6 mg kg−1 day−1), or captopril (1 g/L). Hemodynamic variables were recorded. Cardiac and renal weights, plasma aldosterone, renin activity and urinary catecholamine excretion were measured, as well as cardiac collagen. Blood pressure was lower in stenotic animals treated with CHF-1024 compared to vehicle (161 ± 10 vs 219 ± 10 mmHg, p < 0.01), but LV weight was similar. CHF-1024 elicited a marked dose-dependent attenuation of urinary norepinephrine excretion (1.80 ± 0.18 in controls compared to 0.40 ± 0.14 μg/24 h at the highest dose, p < 0.01) and of LV perivascular fibrosis. Captopril provoked a marked hypotension, reduced cardiac and body weights, plasma aldosterone concentration, dopamine excretion and perivascular collagen. The DA2/α2 agonist CHF-1024 effectively blunts adrenergic drive and cardiac fibrosis in a rat model of pressure overload.

Apoptosis--new opportunities for novel therapeutics for heart diseases.

Abstract: Apoptosis as defined by contemporary science describes a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines, (e.g., TNFα, FAS) neurohormonal factors (angiotension II), cardiotoxic drugs (e.g., doxorubicin) and mechanical, stretch situations. Several complex signal transduction pathways have been implicated in execution of cardiomyocyte apoptosis. Most prominent are: 1) Tyrosine kinase receptors (TRK) induced signaling involving stress or mitogen activated protein kinases (SAPK/MARK) and sphingolipids metabolites (ceramide); 2) G-protein coupled receptor (GPCR) signaling (Gαi, Gαq) and 3) NFK B activation. Apoptosis of cardiac myoctyes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of diverse molecular targets associated with cardiomyocyte apoptosis provide new opportunities for pharmacologic manipulation, that may lead to discovery and development of therapeutic strategies for treatment of heart failure, arrhythmias and myocardial infarction.

Intravenous amiodarone decreases the duration of atrial fibrillation associated with acute myocardial infarction.

Abstract: Purpose: Atrial fibrillation (AF) is a fairly common complication of acute myocardial infarction (AMI) The aim of this study was to examine the safety and efficacy of intravenous amiodarone in converting AF associated with AMI Methods: Seventy patients with AMI complicated with AF were prospectively divided into 3 groups: a) In group D (n = 26), 075 mg digoxin was administered intravenously and thereafter as needed, b) In group AM (n = 16), 300 mg of amiodarone was infused over 2 hours followed by 44 mg/hour for up to 60 hours or until sinus rhythm was restored, c) In group D + AM (n = 28), 075 mg of digoxin was administered (as in group D) for the initial 2 hours followed by amiodarone infusion as in group AM Results: Sinus rhythm was restored: a) by the end of the 2nd hour in 9/26 patients from group D, 4/16 from group AM, and 10/28 from group D + AM (p = NS), b) by the end of the 96th hour, in 18/26 patients from group D, and in all patients from group AM and groupd D + AM The corresponding duration of AF was 51 ± 34 hours, 17 ± 15 hours and 9 ± 13 hours, respectively (F = 154, p < 0001) AF recurred in 9/26, 5/16 and 1/28 patients of groups D, AM and D + AM, respectively (p = 0026) The required dosage of amiodarone was lower in the D + AM group than in the AM group (603 ± 563 mg versus 1058 ± 680 mg, p = 0037) Conclusions: Intravenous amiodarone was well tolerated in patients with AMI complicated by AF and was effective in decreasing the duration of AF However, the combination of amiodarone and digoxin was superior to amiodarone alone in restoring sinus rhythm faster, maintaining sinus rhythm longer, and allowing the use of a lower cumulative amount of amiodarone

Chronic catecholamine depletion switches myocardium from carbohydrate to lipid utilisation

Abstract: Purpose: Chronic cardiac transplantation denervation (i.e., global sympathetic denervation with myocardial catecholamine depletion, plus parasympathetic denervation) is known to inhibit myocardial oxidation of glucose. It is not known whether this is due to increased utilization of lactate, lipid or ketone bodies. The purpose of the present study was to test the hypothesis that the extraction and contribution of blood-borne fatty acids (FA) to overall oxidative energy conversion is increased. Methods: In anaesthetised dogs (control n = 6, cardiac denervated n = 6), we investigated fatty acid (FA) utilization. The studies were made at least four weeks after surgical cardiac denervation. Measurements were made of total FAs and with a radio-labelled tracer (U-14C palmitate). Results: The contribution of FA utilisation to overall substrate oxidation rose from 31% (control) to 48% (cardiac denervated). The increase in the ratio (%) of CO2 production from palmitate oxidation to total CO2 production increased from 4.0 ± 1.8 (control) to 10.6 ± 5.8 (denervated, p = 0.04). The time from uptake of FA to release of CO2 product was unaltered. Conclusion: We conclude that the contribution of FA oxidation to overall energy conversion is increased in chronically denervated hearts, which is postulated to result from a decline in the active form of pyruvate dehydrogenase. This would appear to be a result of chronic catecholamine depletion.

Benidipine, a long-acting Ca channel blocker, limits infarct size via bradykinin- and NO-dependent mechanisms in canine hearts.

Abstract: Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that a long-acting Ca channel blocker, benidipine, increases cardiac NO levels in ischemic canine hearts, suggesting that benidipine may also protect against ischemia and reperfusion injury via bradykinin- and NO-dependent mechanisms. We examined this possibility. In open chest dogs, the left anterior descending coronary artery was perfused with blood through a bypass tube and was occluded for 90 min followed by 6 hours of reperfusion. Infarct size was assessed by TTC staining at 6 hours of reperfusion. When benidipine doses of 50, 100, and 200 ng/kg/min were infused via the bypass tube between 10 min prior to the onset of ischemia and after 60 min of reperfusion, systemic blood pressure did not change significantly. Infarct size decreased with the administration of benidipine (50, 100, and 200 ng/kg/min) when compared to the untreated condition (24.8 ± 2.5, 17.3 ± 3.1, and 16.5 ± 2.0 vs. 43.4 ± 5.6%, respectively) associated with the increased release of NO and bradykinin in the coronary venous blood upon reperfusion. Myeloperoxidase activity of the myocardium increased after 6 hours of reperfusion, which was attenuated by benidipine. The limitation of infarct size and the increase in myeloperoxidase activity were completely blunted by either L-NAME or HOE140. There were no significant differences in collateral blood flow assessed by the microsphere method after 45 min of ischemia for any of the groups. Thus, we conclude that the Ca channel blocker, benidipine, limits infarct size via bradykinin- and NO-dependent mechanisms.

In vitro susceptibility and eradication of Chlamydia pneumoniae cardiovascular strains from coronary artery endothelium and smooth muscle cells.

Abstract: Recovery of viable Chlamydia pneumoniae from atheromas of coronary heart diseases patients has initiated pilot studies to eradicate C. pneumoniae from vascular tissue by antibiotic treatment. To provide data for the selection of effective antibiotics, we investigated the in vitro activity of anti-chlamydial antibiotics to eliminate vascular strains of C. pneumoniae from coronary endothelial and smooth muscle cells, celltypes that are involved in the pathogenesis of atherosclerosis.

Na+ channel activators as positive inotropic agents for the treatment of chronic heart failure.

Abstract: The Na+ channel agonists DPI 201-106, BDF 9148 and BDF 9198 are a new group of positive inotropic agents which increase cardiac contractility in a cAMP independent manner The most likely mechanism by which positive inotropy is mediated is an enhancement of Na+/Ca2+ exchange activity in response to a Na+ channel agonist induced increase in the cardiac myocyte intracellular Na+ concentration While the positive inotropic effect of drugs which exert their effects in a cAMP dependent manner is blunted in failing compared to nonfailing myocardium, the efficacy and potency of Na+ channel agonists is not only maintained, but enhanced in failing myocardium This finding makes these substances interesting for the treatment of patients with heart failure The positive inotropic effects of the Na+ channel agonists, however, are accompanied by a potential increase in the incidence of cardiac arrhythmias These side effects might limit the clinical use of Na+ channel agonists and demand future development of Na+ channel modulators without significant arrhythmogenic effects

Comparison of the effect of perindopril and Acebutolol on cerebral hemodynamics in hypertensive patients

Abstract: Purpose: The aim of the study was to compare effect of perindopril (4 mg once a day) versus acebutolol (400 mg once a day) on cerebral hemodynamics in hypertensive patients

Rationale and Design for the SARIS Trial; Effect of Statin on Atherosclerosis and Vascular Remodeling Assessed with Intravascular Sonography

Abstract: Purpose. The SARIS study (effect of Statin on Atherosclerosis and vascular Remodeling assessed with Intravascular Sonography) is a prospective randomized multicenter trial designed to assess both morphological and functional cardiovascular effects of atorvastatin.

Health Care Expenditure towards the End of Life

Abstract: Over the last thirty years, developed countries have experienced a significant change in the age composition of their population. The relative number of the elderly, in particular those aged 80 and more, has steadily increased—a trend that is expected to continue over the next decades. The main causes of this overall aging of society are the decrease in fertility and the increase in life expectancy, both of which were made possible by an improvement in living conditions and innovations in medicine. Academic and popular writers predict that population aging will substantially affect social, political and economic conditions in the developed world (see, among many others, [1]). Particularly severe consequences are expected for the health care sector, where population aging is blamed for the steady growth of per capita health care expenditure discernible in most industrialized countries over the last thirty years [2]. Since expenditure and age are strongly correlated, it is inferred that future population aging will result in a continued surge in health care expenditure. The argument that health care expenditure will inevitably grow as society ages has been contended. An early dissenter was Fuchs [3] who argued that expenditure and proximity to death, rather than age are causally linked. While age and proximity to death are related, it is the relatively greater number of persons who die in older age cohorts, and not their age per se, that explains the observed correlation between health care expenditure and age. In an empirical analysis recently published in Health Economics we offered support for this contention [4]. We tested the following competing hypotheses. Does health care expenditure during the terminal years increase as a function of proximity to the time of death (hypothesis D), or does it increase as a function of age (hypothesis A)? This test is crucial for predicting the future growth of health care expenditure. If the cost surge were due to age (hypothesis A), then population aging may drive up future per capita health care expenditure. If however the proximity of death is decisive (hypothesis D), then aging cannot be blamed as the principal cost driver. Data

cDNA array hybridization reveals cardiac gene expression in acute ischemic murine hearts.

Abstract: Purpose: Although cDNA array technique has recently become available in the cardiovascular field, it has not yet been established what kind of genes in the myocardium are expressed by acute ischemia. Since many substances contribute to the pathophysiology of acute ischemic hearts, we investigated transcription responses of murine hearts to ischemia using cDNA array representing 18,376 genes. Methods and Results: In 29 male mice, we ligated the proximal site of the left coronary artery for 60 min. In 14 mice, we performed the sham operation without the ligation of the left coronary artery. After 60 min, the hearts were excised to obtain mRNA, and we performed cDNA array analysis. In 18,376 cDNA, 2 known genes were upregulated over 10-fold, 11 known genes were upregulated 5.0-to 9.9-fold, and 32 unknown genes were upregulated over 5.0-fold compared to sham-operated controls. In contrast, 11 known genes and 7 unknown genes were downregulated to levels below 0.2-fold. For 9 of the 13 known genes of which expression was increased as analyzed by cDNA array, subsequent Northern blot analysis also revealed an increase in expression. Conclusion: Using cDNA array analysis we found that cardiac expression of 24 known and 39 unknown genes was modulated by acute ischemic stress, and appeared to be related to the pathophysiology of ischemic hearts. These results show that cDNA array analysis may provide a new molecular insight to the pathophysiology of acute ischemic hearts.

The use of simvastatin in analbuminaemia.

Abstract: Congenital analbuminaemia, a rare disorder associated with defective albumin synthesis, is characterised by hyperlipidaemia. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGRI) to analbuminaemic rats have demonstrated no significant effect on plasma lipids, however no published information regarding HMGRI treatment could be found in human subjects. The efficacy, safety and tolerability of Simvastatin was thus investigated in 2 South African patients with analbuminaemia, a 21 year old Caucasian male (H-B) and a 61 year old black male (A-K). In the case of A-K, the lipid profile responded predictably but H-B responded less that expected from general experience with Simvastatin. Both subjects, however, experienced a three- to five-fold increase in creatine kinase. The use of HMGRI's should thus be used cautiously in these patients and it may be advisable to reserve treatment for secondary prevention.

Has melatonin a future as a cardioprotective agent

Abstract: Melatonin is a hormone that is released from the pineal gland, and is best known therapeutically for its efficacy to combat sleeping disorders, in particular those caused by jet-lag. In the last decennium, however, the interest in the hormone has increased, mainly following the discovery of its antioxidant properties [1]. Melatonin is most effective in scavenging hydroxyl radicals (• OH), which are formed from superoxide-anion and hydroygenperoxide (H2O2) via the iron-catalyzed Haber-Weiss reaction and from H2O2 via the Fenton reaction. In addition, there is evidence that melatonin is also effective against nitric oxide (NO), the peroxy nitrite anion (ONOO−) and its metabolites, and H2O2, either directly or indirectly via increasing the activity of other antioxidant enzyme systems (e.g. gluthathione peroxidase). In addition to its antioxidant effects, melatonin possesses several other properties, such as inhibition of peripheral sympathetic responses, stimulation of [Ca2+] dependent ATPase in myocardial sarcolemma, decrease of the voltage-operated Ca2+ dependent channels and vascular binding sites that are functionally linked to vasoconstriction and vasodilation. The scavenging properties of melatonin have given rise to a large number of investigations that have tested its ability to limit ischemia-reperfusion injury. Several studies have subsequently shown that, when administered in pharmacological doses, melatonin is capable of limiting ischemia-reperfusion injury in a number of organs, even when high levels of other endogenous antioxidants such as vitamins E and C and gluthathione are present. The initial studies focussed on limitation of reperfusion injury in other organs than the heart and used treatment regimens that were started before the onset of ischemia and used doses considerably higher than the physiological plasma concentrations (5–15 nM, 1–3 ng/ml). For instance, Bertuglia et al. [2] showed that intravenous administration of 0.6 mg/ 100 g body weight over a 5 min period at 10 min before and at the end of a 30-min episode of ischemia of the cheek pouch in hamsters, prevented ischemia-reperfusion injury, assessed by inhibition of microvascular edema formation, reduction of the number of leukocytes sticking to venules and attenuation of the marked decrease in perfused capillary length. Although the protection by melatonin involved free radical scavenger activity, other mechanisms could not be ruled out, because melatonin produced a significant reduction in heart rate and a tendency of blood pressure to decrease. The authors suggested that this may have been caused by a modulating effect of melatonin on calcium influx in cardiac and vascular muscle cells, not necessarily related to free radicals. In another study in rats pretreated with 5 mg/kg melatonin administered intragastrically, there was not only a reduction in gastric lesions after the celiac artery was occluded for 30 min and reperfused for 48 hours, but also an attenuation in the fall in gastric blood flow [3]. Although there was a reduction in circulating free radicals, the latter finding also suggests the involvement of vascular factors, such as the release of prostaglandins or nitric oxide, well-known mediators of gastroprotection by other hormones [4]. Also in the study by Borlongan et al. [5], who showed increased glial cell survival up to 19 days after a 1-hour middle cerebral artery occlusion in rats, was melatonin (26 μmol p.o. ≈ 6.0 mg) already present before the onset of ischemia, implying that protection may already have occurred during ischemia. In contrast, Ustundag et al. [6] administered up to 20 mg/kg melatonin by intraperitoneal injection at the end of a 30 min mesenteric artery occlusion, followed by intramuscular administration during the following two days and observed an increase in glutathione peroxidase and superoxide dismutase levels. Unfortunately these investigators did not determine whether these increased levels actually decreased tissue damage. The effect of melatonin on myocardial reperfusion injury has received attention only in recent years. These studies have emphasized the effect of melatonin on the incidence of reperfusion arrhythmias, stunning and limitation of infarct size. It is surprising that it has taken so long before the antiarrhythmic effects of melatonin were studied in ischemia-reperfusion models as it is known for more than 20 years that melatonin may exert antiarrhythmic activity by decreasing cardiac sympathetic activity [7,8]. Tan et al. [9] have reported that melatonin reduced the incidence of ventricular arrhythmias and ventricular fibrillation during ischemia and reperfusion in isolated rat hearts in which a coronary artery was temporarily occluded. Kaneko et al. [10] showed a reduced duration of ventricular tachycardia (VT) and ventricular fibrillation (VF), and an improved

Metabolism of hepatocyte growth factor in the heart in patients with coronary artery disease: implication for coronary arteriosclerosis.

Abstract: Purpose: HGF, one of endothelium-specific growth factors, might contribute to the repair process of vascular endothelial cell damage, suggesting that serum HGF concentration may be elevated in patients with arteriosclerosis. However, the cardiac metabolism of HGF has not been examined in patients with coronary artery disease (CAD). We examined the levels of hepatocyte growth factor (HGF) in the coronary circulation and its correlation with the severity of arteriosclerosis in patients with CAD. Methods: We measured serum HGF concentration obtained from the coronary sinus (CS) and ascending aorta (AA) in patients with atherosclerotic CAD (Group E, n = 33) or vasospastic angina (Group V, n = 26), or normal control subjects (Group N, n = 12). In Group E, the severity of coronary artery stenosis was evaluated using the Gensini's score. Results: Serum HGF concentrations (ng ml) in the CS were 0.112 ± 0.008 in Group E (p < 0.001 vs. Group V, p < 0.001 vs. Group N), 0.197 ± 0.012 in Group V (p = 0.031 vs. Group N), and 0.245 ± 0.021 in Group N. Serum HGF concentrations in the AA were 0.282 ± 0.014 in Group E (p = 0.045 vs. Group V, p = 0.021 vs. Group N), 0.246 ± 0.012 in Group V, and 0.237 ± 0.009 in Group N. Serum HGF extraction in the heart (HGF in the AA-HGF in the CS) in Group E (0.170 ± 0.018) was significantly higher compared with in Group V (0.049 ± 0.011) or Group N (0.008 ± 0.005). There was a significant negative correlation between the severity of coronary arteriosclerosis and serum HGF concentration in CS (r = −0.66, p < 0.001), and a significant positive correlation between the severity of coronary arteriosclerosis and HGF extraction in the heart (r = 0.75.p < 0.001). Conclusions: We conclude that the difference of HGF levels between CS and AA in patients with CAD are decreased, and extent of decreases in HGF levels correlates with the severity of coronary arteriosclerosis. The abnormality of HGF metabolism in the heart may contribute to the progression of coronary arteriosclerosis.

Differential ability of human endothelial cells to internalize and express exogenous DNA

Abstract: Vascular endothelium gene expression regulates blood-vessel wall interactions, vascular permeability, smooth muscle cell growth and tone. The possibility to introduce exogenous DNA or RNA sequences in endothelial cells represents a novel therapeutic approach of vascular disease. The aim of the work was to investigate the ability of endothelial cells to internalize and express exogenous DNA sequences. Human umbilical vein endothelial cells (HUVEC) were transfected with either a 780 bp fluorescein-labeled DNA (FITC-DNA) or pEGFP-C1 plasmid encoding for a green fluorescent protein (GFP), using the cationic liposome DOTAP as transfection reagent. The transfected cell population was passed through a FACScan apparatus and percentage of fluorescent cells was determined using a FACScan analysis programme. The SW620 tumor-derived cell line was used as control. The percentage of FITC-DNA positive cells was 66.0% for HUVEC and 45.0% for SW620 cells. On the contrary, the percentage of GFP-positive cells was 13.8% and 43% for HUVEC and SW620, respectively. By increasing the amount of DNA as well as the protocol of administration the percentage of GFP-positive HUVEC was enhanced suggesting a rapid degradation of DNA in the HUVEC cytoplasm.