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We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ETB-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ETB-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ETB-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ETB-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.

Oxidative stress is linked to coronary artery disease and is a major mechanism in contrast-induced nephropathy. Trans-radial approach in coronary angiography (CA) with minimized peri-procedural bleeding is expected to reduce acute kidney injury incidence. In the present study, oxidative stress patterns observed in radial CA and their associations with early manifestations of kidney injury are described. A total of 20 stable coronary disease patients submitted to CA and 17 sex-matched patients undergoing computed tomography for myoskeletal reasons were enrolled. Reduced glutathione, catalase, thiobarbituric acid reactive species (TBARS) levels and total anti-oxidant status were measured at various time points postangiography. In ischemic patients baseline TBARS levels were 2-fold lower compared to controls, while carbonyls levels were 35% higher. Glutathione was almost 4-fold lower than the control group. Glutathione and lipid peroxidation in ischemic patients gradually increased after contrast medium administration and reached 180% (P

We review the role of endothelin (ET) A-receptors (R) on the coronary circulation. ET-1 maintains the normal coronary artery tone. ET-1 plasma levels are increased during and after coronary angioplasty and this increase is related to myocardial ischaemia rather than to mechanical artery injury. ETAR antagonists inhibit coronary artery vasoconstriction induced by ET release after coronary angioplasty in humans. ET promotes neointimal formation and ETAR antagonism has been shown to inhibit restenosis after angioplasty in the animal model but not in humans. ETAR blockade increases coronary blood flow, dilates distal coronary arterial segments and decreases coronary vascular resistance. Coronary collaterals are less sensitive than other coronary vessels to ET-1. ETAR blockade decreases collateral blood flow and, consequently, perfusion of the ischemic myocardium.

Chronic skeletal muscle ischemia confers cytoprotection to the ventricular myocardium during infarction, but the underlying mechanisms remain unclear. Although neovascularization in the left ventricular myocardium has been proposed as a possible mechanism, the functional capacity of such vessels has not been studied. We examined the effects of chronic limb ischemia on infarct size, coronary blood flow, and left ventricular function after ischemia-reperfusion. Hindlimb ischemia was induced in 65 Wistar rats by excision of the left femoral artery, whereas 65 rats were sham operated. After 4 wk, myocardial infarction was generated by permanent coronary artery ligation. Infarct size was measured 24 h postligation. Left ventricular function was evaluated in isolated hearts after ischemia-reperfusion, 4 wk after limb ischemia. Neovascularization was assessed by immunohistochemistry, and coronary flow was measured under maximum vasodilatation at different perfusion pressures before and after coronary ligation. Infarct size was smaller after limb ischemia compared with controls (24.4 ± 8.1% vs. 46.2 ± 9.5% of the ventricle and 47.6 ± 8.7% vs. 80.1 ± 9.3% of the ischemic area, respectively). Indexes of left ventricular function at the end of reperfusion (divided by baseline values) were improved after limb ischemia (developed pressure: 0.68 ± 0.06 vs. 0.59 ± 0.05, P = 0.008; maximum +dP/d t: 0.70 ± 0.08 vs. 0.59 ± 0.04, P = 0.004; and maximum −dP/d t: 0.86 ± 0.14 vs. 0.72 ± 0.10, P = 0.041). Coronary vessel density was markedly higher ( P = 0.00021) in limb ischemic rats. In contrast to controls ( F = 5.65, P = 0.00182), where coronary flow decreased, it remained unchanged ( F = 1.36, P = 0.28) after ligation in limb ischemic rats. In conclusion, chronic hindlimb ischemia decreases infarct size and attenuates left ventricular dysfunction by increasing coronary collateral vessel density and blood flow.

Few studies have addressed the impact of moderate unsupervised everyday physical activity in patients with chronic heart failure (CHF).We investigated the effects of a 12-week walking programme as the sole exercise intervention on heart rate recovery (HRR), index of the autonomic system equilibrium, serum modulators of endothelial function (i.e. asymmetric dimethylarginine (ADMA) and homocysteine), markers of inflammation and oxidative stress and quality of life measures (i.e. SF-36 and the Zung depression scale) in CHF patients.Twenty-eight stabilized CHF patients of ΝYHΑ class II and III volunteered to participate either in the exercise (n = 18) or in the non-exercise (n = 10) groups. Ten age-matched healthy volunteers provided reference values. The exercise programme consisted of unsupervised 40-minute walking for five days per week.Repeated measures ANOVA revealed significant improvements in HRR (p 0.001) in the exercise patients compared to their non-exercise counterparts. ADMA levels in CHF patients at baseline were found higher than the healthy reference volunteers (p 0.03), while a decrease in ADMA levels after walking was associated with HRR changes (r = 0.74, p = 0.007). Homocysteine levels both at baseline and at the end of the walking intervention decreased in the exercise group, but were still higher than in the healthy individuals. Average walking distance positively correlated with homocysteine decrease (p 0.05). Total SF-36 score significantly improved (p 0.02) mainly due to enhancements in the physical component score (p 0.026).A 12-week unsupervised walking programme exhibits a pronounced HRR amelioration, possibly attenuates endothelial damage and induces a concomitant improvement in perceived quality of life in CHF patients.

Backround Statin treatment is considered as first line therapy in patients with atherosclerotic disease. We evaluated the effect of pre-treatment with statins on carotid plaque infiltration by macrophages and on the circulating levels of proinflammatory cytokines in patients who underwent carotid endarterectomy. Patients and Methods One hundred fourteen patients were enrolled; 89 men and 25 women (mean age 67±8 years; range 42-83 years). Fifty three patients (46%) were on statin treatment at least 3 months before endarterectomy and 61 (54%) had never received statin treatment. The serum levels of high sensitivity C reactive protein (hsCRP), serum amyloid A (SAA), tumor necrosis factor α (TNFα), interleukin (IL)-1β and IL-6 were evaluated preoperatively. The intensity of macrophage infiltration was evaluated by immunochemistry, using the monoclonal antibody CD 68. The area of the plaque covered by macrophages was measured as a proportion of the whole plaque area, using a custom designed image tool analysis. Results Patients on statins had lower serum total cholesterol levels (172±50 vs 194±35 mg/dl, p= 0.014), lower low density cholesterol levels (103±44 vs 123±31 mg/dl, p= 0.010) and lower serum hsCRP levels (1.8 [1.1-3.4] vs 3.4 [1.3-4.9] mg/l, p= 0.03), while SAA, TNFα, IL-6 and IL-1β levels did not differ between the 2 groups. The infiltration of atherosclerotic plaque by macrophages was similar in statin treated patients and in controls (0.55±0.15% vs 0.49±0.19%, p= 0.21). Conclusion Patients on statins have similar macrophage accumulation in their carotid atherosclerotic plaques compared with patients not on statins. Inflammatory markers were also similar in both groups except for hsCRP which was significantly lower in those taking statins.

Background: The aim of this study was to investigate the presence, etiology and clinical significance of elevated troponin I in patients with acute upper or lower limb ischemia. The high sensitivity and specificity of cardiac troponin for the diagnosis of myocardial cell damage suggested a significant role for troponin in the patients investigated for this condition. The initial enthusiasm for the diagnostic potential of troponin was limited by the discovery that elevated cardiac troponin levels are also observed in conditions other than acute myocardial infarction, even conditions without obvious cardiac involvement. Patients and Methods: 71 consecutive patients participated in this study. 31 (44%) of them were men and mean age was 75.4 ± 10.3 years (range 44–92 years). 60 (85%) patients had acute lower limb ischemia and the remaining (11; 15%) had acute upper limb ischemia. Serial creatine kinase (CK), isoenzyme MB (CK-MB) and troponin I measurements were performed in all patients. Results: 33 (46%) patients had elevated peak troponin I (> 0.2 ng/ml) levels, all from the lower limb ischemia group (33/60 vs. 0/11 from the acute upper limb ischemia group; p = 0.04). Patients with lower limb ischemia had higher peak troponin I values than patients with upper limb ischemia (0.97 ± 2.3 [range 0.01–12.1] ng/ml vs. 0.04 ± 0.04 [0.01–0.14] ng/ml respectively; p = 0.003), higher peak CK values (2504 ± 7409 [range 42–45 940] U/ml vs. 340 ± 775 [range 34–2403] U/ml, p = 0.002, respectively, in the two groups) and peak CK-MB values (59.4 ± 84.5 [range 12–480] U/ml vs. 21.2 ± 9.1 [range 12–39] U/ml, respectively, in the two groups; p = 0.04). Peak cardiac troponin I levels were correlated with peak CK and CK-MB values. Conclusions: Patients with lower limb ischemia often have elevated troponin I without a primary cardiac source; this was not observed in patients presenting with acute upper limb ischemia. It is very important for these critically ill patients to focus on the main problem of acute limb ischemia and to attempt to treat the patient rather than the troponin elevation per se. Cardiac troponin elevation should not prevent physicians from providing immediate treatment for limb ischaemia to these patients, espescially when signs, symptoms and electrocardiographic findings preclude acute cardiac involvement.

Sildenafil was the first oral compound to be approved for the treatment of erectile dysfunction. In this paper, we review the current knowledge of the effects of sildenafil on myocardial infarction and sudden cardiac death. The first factor we examine is the sexual activity itself. As several studies have shown, the relative risk for an acute coronary syndrome during intercourse is not very high. Several studies examining the effects of sildenafil on mortality have been published during recent years. The great majority of these studies found that sildenafil is not an extra risk factor for an acute coronary syndrome or sudden cardiac death. In 1997, the rate of myocardial infarction in men 55-64 years of age was 1542 per 1,000000 in the US. According to this, the expected number of deaths as a result of myocardial infarction in patients 55-64 years of age receiving sildenafil, in the 24-hour period after use, from late March 1997 to mid November 1998, should have been 52. Instead, the number of reported deaths were only 15. One very optimistic finding was that sildenafil not only does not increase mortality, but in fact 'preconditions' the heart and has a cardioprotective effect. Besides, many studies have shown that sildenafil does not reduce the exercise tolerance in men with known coronary artery disease. As far as BP is concerned, the differences before and after the use of sildenafil are not clinically significant. The only contraindications for sildenafil are co-administration with alpha-adrenoceptor antagonists or with nitric oxide donors. According to the most recent studies, isoform 5 of phosphodiesterase has also been detected in the myocardium and controls the soluble pool of 3', 5'-cyclic guanosine monophosphate (cGMP). Sildenafil is very specific for cGMP but it may increase cyclic adenosine monophosphate in the myocardium indirectly. This does not occur with small therapeutic doses of the drug. There is some dispute regarding the association of sildenafil with arrhythmias, where the available evidence is not clear. However, there are suspicions that sildenafil may cause sympathetic activation. The overall conclusion is that sildenafil is a safe drug and that its appropriate use does not seem to increase the risk for myocardial infarction or sudden cardiac death.

Asynchronous depolarization and contraction sequence, secondary to intraventricular conduction defects or to permanent right ventricular apical pacing, is associated with adverse effects that may be clinically evident in the failing heart. Experimental and clinical studies have suggested that asynchronous ventricular contraction deteriorates left ventricular performance and induces unfavourable left ventricular remodelling. Although such contraction does not appear to affect resting coronary artery blood flow, it increases endomyocardial pressure during diastole and decreases regional myocardial perfusion in the interventricular septum. The magnitude of these effects may correlate with the duration of the asynchrony. Despite these detrimental effects, there is no evidence that ventricular asynchrony reduces collateral myocardial blood flow, myocardial oxygen consumption or cardiac efficiency, neither in patients with normal coronary arteries, nor in patients with coronary artery disease. Furthermore, in patients with acute ischaemic syndromes, ventricular asynchrony exerts a neutral effect on the ischaemic myocardium. Cardiac resynchronization therapy improves left ventricular systolic and diastolic function without an increase in myocardial oxygen consumption or energy cost. This therapy may decrease the inhomogeneity in regional oxidative metabolism, myocardial perfusion and cardiac efficiency. Further experimental and clinical studies are needed on this area.

The elderly constitute an increasingly important sector of patients with acute coronary syndromes (ACS), although they have been under-represented in many therapeutic trials. Elderly patients with ACS usually have more complex co-morbidities and worse outcomes than their younger counterparts, and they are less likely to undergo revascularisation or to receive short- and long-term evidence-based medications. The most common ACS in the elderly is non-ST-segment elevation myocardial infarction (STEMI), which is associated with high mortality. For this reason, elderly patients with non-STEMI and unstable angina should be treated invasively early in the course of the episode. In elderly patients with STEMI, primary angioplasty seems to be more effective than fibrinolysis, and in patients aged >85 years a more conservative approach to fibrinolysis is also warranted because of the higher risk for cerebral haemorrhage. Therefore, angioplasty should be preferred when feasible, although more trials are needed before this strategy can definitely be documented as the preferred option. Drug-eluting stents afford greater benefit than bare metal stents in elderly patients and are more cost effective. After fibrinolysis, low-molecular-weight heparin appears to be superior to unfractionated heparin in elderly patients with STEMI but major bleeding and intracranial haemorrhages occur more frequently, especially in women aged >75 years. It is very important to understand that the elderly with ACS constitute a subgroup of atherosclerotic patients for whom decision making must be guided by the patients''physiological age' (determined by their physical condition and other co-morbidities) and not strictly by their 'chronological age'.

Objective: Attempts to demonstrate preconditioning during repeated angioplasty balloon inflations (BIs) have not been universally successful. The main obstacle is that the first BI is unreliable, due to the variable degrees of occlusion by the deflated balloon. In the present study, we examined whether ST segment elevation decreases and evaluated its relation to collateral recruitment during repeated angioplasty BIs in the pig. Methods and Results: Twenty male pigs, 7 months old, under general anesthesia, underwent 3 repeated BIs of 120 s, with a 5-min interval between them, in the left anterior descending artery or the right coronary artery. A pressure wave wire was used for the measurement of coronary wedge pressure and to obtain the intracoronary ST segment elevation. Intracoronary ST segment elevation was 1.97 ± 0.76 mV during the 1st BI, 2.09 ± 0.82 mV during the 2nd BI and 1.84 ± 0.82 mV during the 3rd BI (p = n.s.). Coronary wedge pressure was 12 ± 6, 18 ± 18 and 20 ± 20 mm Hg (p < 0.05 vs. 1st BI) during the 3 BIs, respectively. Conclusion: Repeated BIs do not diminish ST segment elevation in the pig model, even though coronary collateral recruitment is promoted.

Aims Sympathetic activation during myocardial ischemia enhances arrhythmogenesis, but the underlying pathophysiologic mechanisms remain unclear. We investigated the central sympathetic effects on ventricular repolarization during the early-period post-coronary artery occlusion. Main methods We studied 12 Wistar rats (254 ± 2 g) for 30 min following left coronary artery ligation, with (n = 6) or without (n = 6) pretreatment with the central sympatholytic agent clonidine. Mapping of left and right ventricular epicardial electrograms was performed with a 32-electrode array. As an index of sympathetic activation, heart rate variability in the frequency domain was calculated. Heart rate and repolarization duration were measured with a custom-made recording and analysis software, followed by calculation of intra- and inter-ventricular dispersion of repolarization. Key findings Heart rate and heart rate variability indicated lower sympathetic activation in clonidine-treated rats during ischemia. Repolarization duration in the left ventricle prolonged after clonidine at baseline, independently of heart rate, but no differences were present 30 min post-ligation. Dispersion of repolarization in the right ventricle remained stable during ischemia, whereas it increased in the left ventricle, equally in both groups. A similar trend was observed for inter-ventricular dispersion, without differences between groups. Significance In addition to intra-ventricular repolarization-dispersion, anterior-wall myocardial ischemia may also increase inter-ventricular repolarization-dispersion. Progressive central sympathetic activation occurs during myocardial ischemia, but it does not affect intra- or inter-ventricular dispersion of ventricular repolarization during the early phase. Further research is warranted on the potential effects during subsequent time-periods.

To assess the efficacy and safety of transradial approach regardless of the Allen's test results for coronary angiography and angioplasty.Prospective data collection of 1035 consecutive patients who underwent coronary angiography with or without ad hoc angioplasty through the radial approach was conducted. Baseline demographic and procedural data were recorded. Allen's test was evaluated in all subjects before the procedure and catheterization was performed from the radial approach irrespective of the results. Radial artery patency was evaluated at discharge clinically, or by Doppler examination if pulse was not palpable. A total of 256 patients (24.7%) were found to have a negative Allen's test and 779 patients (75.3%) had a positive test. The baseline and procedural characteristics were similar in both groups. No significant differences in complications were reported. Radial artery thrombosis was observed in 6.2% of the negative Allen's test group and 4.8% of the positive Allen's test group (P=.85), but this was clinically silent even in the negative Allen's test group.Transradial approach for coronary angiography and ad hoc angioplasty can be performed with similar efficacy and safety regardless of the Allen's test results before the procedure.

Aim We examined whether there is a differential effect of endothelin-A antagonism on coronary artery compliance in type 2 diabetes mellitus compared to non-diabetic patients. Patient and methods We examined 32 patients, 11 type 2 diabetes mellitus and 21 non-diabetic patients, with atherosclerotic epicardial arteries free of significant luminal stenoses. Intracoronary BQ-123 (6 μmol), an endothelin-A receptor antagonist, was infused over 20 min. The artery lumen area in the proximal arterial segment was measured at end diastole and end systole before and after BQ-123 administration using an intravascular ultrasound catheter. Calculations were made of normalized arterial compliance index, in mm Hg −1 × 10 3 and of arterial stiffness index β. Results Pulse pressure and heart rate did not change after BQ-123. In type 2 diabetes mellitus, normalized compliance index decreased from 1.79±1.36 at baseline to 1.29±0.82 after BQ-123 administration, whereas in non-diabetic patients it increased from 2.10±1.36 to 3.00±2.07 ( p F =6.39, p =0.02). In type 2 diabetes mellitus, β index increased from 1.97±0.53 to 2.46±0.95, whereas in non-diabetic patients it decreased from 1.83±0.95 to 1.63±0.84 ( F =7.80, p =0.009). Big endothelin-1 at baseline was correlated with the baseline β index ( p r =0.68). Conclusions Big endothelin-1 is correlated with the coronary artery stiffness. The effect of endogenous endothelin-1 on coronary artery stiffness is impaired in type 2 diabetes mellitus. This may have important therapeutic implications with respect to the introduction of endothelin receptor antagonists as cardiovascular therapeutic agents.

Ventricular remodeling is a common corollary of myocardial infarction. We hypothesized that this process may be attenuated by growth hormone, administered as a single high-dose, selectively in the infarct zone, early postmyocardial infarction.In 35 pigs (29+/-4 kg), myocardial infarction was generated by inflation of an over-the-wire angioplasty balloon in the circumflex artery for 60 min and 5 further pigs were sham-operated. Ten minutes after reperfusion, the pigs were randomized (2:1) to either growth hormone (1 IU/kg) (n=23) or normal saline (n=12), delivered via the balloon catheter. All survivors were treated with captopril and were sacrificed 4 weeks after myocardial infarction.Compared to controls, growth hormone-treated animals displayed lower heart weight (4.1+/-0.5 g/kg body weight, versus 3.4+/-0.4 g/kg, respectively, p=0.003) and dimensions (left ventricular short axis diameter 46+/-7 mm versus 37+/-6 mm, p=0.01; right ventricular short axis diameter 38+/-7 mm versus 30+/-5 mm p=0.001). Growth hormone increased wall thickness in the infarct (6.0+/-1.8 in controls versus 9.9+/-3.7 in treated animals, p=0.004) and non-infarct zones (10.6+/-1.8 in controls versus 15.5+/-3.8 in treated animals, p=0.0006) and produced higher (p0.05) microvascular density in both zones.Intracoronary administration of growth hormone attenuates left and right ventricular remodeling by inducing hypertrophy and by enhancing angiogenesis.

Objective : Endothelin-1 (ET-1) production increases during acute myocardial infarction (MI) and may contribute to the genesis of ventricular tachycardia (VT) and ventricular fibrillation (VF). However, the antiarrhythmic effects of ET-1 receptor blockade, examined shortly after MI, have been debated. In the present study, we examined the effects of such treatment on VT/VF during the first 24 h post-MI. Methods : Thirty-five Wistar rats (223 ± 22 g) were randomly allocated to either the ET-1 receptor-A (ETA) antagonist BQ-123 (0.4 mg/kg, BQ-123 group, n = 17), or normal saline (control group, n = 18) and were subjected to coronary artery ligation. A single-lead electrocardiogram was continuously recorded for 24 h post-MI, using an implanted telemetry system, and episodes of VT/VF were analyzed. Monophasic action potential (MAP) recordings were obtained from the left (LV) and right (RV) ventricular epicardium at baseline, 5 min after treatment and 24 h post-MI. Results : There were 15.94 ± 19.35 episodes/h/rat of VT/VF in the control group and 1.66 ± 2.22 in the BQ-123 group ( p = 0.010), resulting in a lower ( p = 0.030) arrhythmic mortality in treated animals. The mean episode duration was 7.40 ± 7.16 s for the control group and 2.30 ± 1.37 s for the BQ-123 group ( p = 0.011). The maximum decrease in VT/VF was observed during the 1st, 5th and 6th hours post-MI. In the control group, LV MAP duration increased 24 h post-MI, displaying an increased beat-to-beat variation, but remained unchanged in the BQ-123 group. Conclusion : Acute ETA blockade reduces the incidence of VT/V F during the first 24-h post-MI in the rat, through a decrease in the dispersion of repolarization.

paradoxic beneficial effect of obesity in patients undergoing percutaneous coronary intervention: the obesity paradox? (abstr). J Am Coll Cardiol 2001;37(suppl A):22A. 12. Gurm HS, Whitlow P, Kip KE. The impact of body mass index (BMI) on early outcome after percutaneous coronary interventions (PCI) (abstr). J Am Coll Cardiol 2001;37(suppl A):22A. 13. Thel MC, Califf RM, Tardiff BE, Gardner LH, Sigmon KN, Lincoff AM, Topol EJ, Kitt MM, Blankenship JC, Tcheng JE, for the IMPACT-II Investigators. Timing of and risk factors for myocardial ischemic events after percutaneous coronary intervention (IMPACT-II). Am J Cardiol 2000;85:427–434. 14. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. BMJ 1984;288:1401–1404. 15. Folsom AR, Stevens J, Schreiner PJ, McGovern PG. Body mass index, waist/hip ratio, and coronary heart disease incidence in African Americans and whites. Atherosclerosis Risk in Communities Study Investigators. Am J Epidemiol 1998;148:1187–1194. 16. Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, Willett WC, Manson JE. Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:1843–1848.

Purpose: Raloxifene is a selective estrogen receptor modulator and an attractive alternative to estrogen replacement as it obviates the need for a progestin and does not increase C-reactive protein levels. We compared the effects of simvastatin and raloxifene treatments on the lipid profile, the levels of adhesion molecules and the endothelium dependent and independent vasoreactivity. Subjects & Methods: We treated 12 postmenopausal women with hypercholesterolemia and coronary artery disease with raloxifene 60 mg/day and simvastatin 20 mg/day in a randomized, double-blind, crossover study. Each treatment period was 8 weeks long with a 4-week washout interval. Plasma lipids and cellular adhesion molecules were evaluated and peripheral blood flow studies with venous occlusion plethysmography were performed. Results: Both simvastatin and raloxifene significantly reduced total [33% (27–40), 12% (0–24)] and LDL [44% (36–52), 16% (0–33)] cholesterol compared to baseline values (p < 0.05) but simvastatin was more effective than raloxifene (p < 0.005). None of the treatments had any significant effect on HDL cholesterol and triglyceride levels. Only raloxifene significantly reduced Lp(a) [18% (1–36)] and ICAM-1 [17% (8–25)] and VCAM-1 [24% (15–33)] plasma levels compared to baseline (p = 0.019, p < 0.0001 and p = 0.003, respectively). Hyperemic blood flow response on raloxifene was significantly higher compared to baseline [52% (0–105)], (p < 0.05), whereas no significant change was noted on simvastatin. Endothelium independent blood flow induced by nitroglycerine was not influenced by either active treatment. Conclusions: Raloxifene administration is associated with lower ICAM-1, VCAM-1 and Lp(a) plasma levels and enhanced endothelium dependent dilation compared to simvastatin although simvastatin is more powerful in total and LDL cholesterol reduction.

Selective endothelin receptor-A antagonists are a promising new treatment in patients with heart failure and/or pulmonary hypertension. Animal studies have suggested that these agents may have additional cardiac electrophysiologic actions, however, no data exist in man. We examined the effects of acute endothelin receptor-A blockade on the sinus node, the atrioventricular node and on the ventricular myocardium, in patients with single-vessel coronary artery disease and preserved left ventricular function. The selective endothelin receptor-A antagonist BQ-123 was administered by the intracoronary route, in order to achieve maximum local cardiac effects. After endothelin receptor-A blockade, QT interval increased from 373 ± 30 msec (mean ± SD) to 395 ± 20 msec (p < 0.01) and QTc interval increased from 394 ± 36 msec to 421 ± 28 msec (p < 0.01). QT-dispersion, calculated from 12-lead ECG, decreased from 40 ± 18 msec to 24 ± 8 msec (p < 0.01) and QTc-dispersion decreased from 44 ± 20 msec to 26 ± 9 msec (p < 0.05). These changes were evident only after infusion in the left, but not in the right coronary artery. No effect was found on the sinus node, the atrioventricular node, or the ventricular effective refractory periods. We conclude that selective endothelin receptor A blockade lengthens ventricular repolarization and decreases its inhomogeneity. Further studies are needed to evaluate possible antiarrhythmic actions of this class of agent.

Sympathetic activation during acute myocardial infarction is an important arrhythmogenic mechanism, but the role of central autonomic inputs and their modulating factors remain unclear. Using the in vivo rat-model, we examined the effects of clonidine, a centrally-acting sympatholytic agent, in the presence or absence of myocardial endothelin-B (ETB) receptors. We studied wild-type (n=20) and ETB-deficient rats (n=20) after permanent coronary ligation, with or without pretreatment with clonidine. Cardiac rhythm was continuously recorded for 24 hours by implantable telemetry devices, coupled by the assessment of autonomic and heart failure indices. Sympathetic activation and arrhythmogenesis were more prominent in ETB-deficient rats during the early phase post-ligation. Clonidine improved these outcomes throughout the observation period in ETB-deficient rats, but only during the delayed phase in wild-type rats. However, this benefit was counterbalanced by atrioventricular conduction abnormalities and by higher incidence of heart failure, the latter particularly evident in ETB-deficient rats. Myocardial ETB-receptors attenuate the arrhythmogenic effects of central sympathetic activation during acute myocardial infarction. ETB-receptor deficiency potentiates the sympatholytic effects of clonidine and aggravates heart failure. The interaction between endothelin and sympathetic responses during myocardial ischemia/infarction and its impact on arrhythmogenesis and left ventricular dysfunction merit further investigation.

Endothelin (ET) exerts a tonic, stiffening effect on the common carotid artery in rats in vitro. This effect is mediated via the ET(A) receptor. The aim of this study was to examine the acute effects of ET(A) receptor antagonism on coronary artery compliance in humans. We examined 22 patients with stable angina after diagnostic coronary arteriography. Intracoronary BQ-123 (6 micromol), an ET(A) receptor antagonist (14 patients), or saline (8 patients), was infused in an artery without significant lesion over 20 min. The artery lumen area in the proximal arterial segment was measured at end diastole and end systole before and after BQ-123 or saline administration using an intravascular ultrasound catheter. Calculations were made of absolute (in mm(2)/mmHg x 10(3)) and normalized compliance index (in mmHg(-1) x 10(3)). Pulse pressure decreased from 64+/-21 to 61+/-17 mmHg after BQ-123 administration and increased from 59+/-16 to 68+/-20 mmHg after saline administration (F=9.54, P=0.006). The respective changes in absolute compliance index were from 24+/-18 to 39+/-25 and from 19+/-15 to 14+/-17 (F=6.43, P=0.02). Normalized compliance index changed from 2.5+/-2.0 to 3.6+/-2.4 and from 2.7+/-2.6 to 1.6+/-1.8 (F=11.92, P=0.002) respectively, in the two groups. Acute ET(A) receptor antagonism improves coronary artery compliance in coronary artery disease patients.

Flondell-Site et al in this issue of Angiology report that besides abdominal aortic aneurysm (AAA) diameter (P 1⁄4 .0019), endothelin-1 (ET-1) levels (P 1⁄4 .0230) were significant predictors of AAA growth in 178 patients with AAA followed conservatively (mean: 2.9 + 1.6 years). In univariate analysis, ET-1 levels also predicted death or need for AAA surgery. These results suggest an alternative/additional predictor of AAA growth and rupture risk besides AAA diameter. Currently, the main criterion for AAA repair is an AAA diameter 5.5 cm. The 5.5-cm diameter threshold is the size when the AAA rupture rate balances the mortality rates of elective AAA repair (3%). However, some AAAs rupture when they are smaller and many are discovered after they have exceeded this critical diameter but have not ruptured. It therefore seems that size alone is not sufficient to assess AAA rupture risk. The discovery of alternative predictors of AAA growth and rupture risk holds implications for a more appropriate (earlier/later) surgical management of AAAs. This Editorial discusses potential predictors of AAA growth and rupture risk besides AAA diameter and ET-1.

OBJECTIVE—To examine the contribution of endothelin type A (ETA) receptor stimulation by endogenously generated endothelin-1 (ET-1) to the maintenance of coronary vascular tone in humans. DESIGN—Controlled clinical study. SETTING—Tertiary cardiovascular referral centre. PATIENTS—14 subjects were studied, seven with normal coronary arteries and seven with coronary artery disease, mean (SEM) age, 53 (2) years. INTERVENTIONS—After diagnostic coronary arteriography, BQ-123 (a selective ETA receptor antagonist; 100 nmol/min) in 0.9% saline, was infused into the left coronary artery at a rate of 1 ml/min for 60 minutes. Eight control subjects received saline alone. MAIN OUTCOME MEASURES—Blood flow velocity in the left anterior descending coronary artery, measured using a Doppler flow guidewire; coronary arteriography performed at baseline and immediately at the end of the BQ-123 or saline infusion to measure the diameter of proximal and distal left anterior descending coronary artery segments. RESULTS—The diameter of the proximal segment increased by 6 (2)%, while that of the distal segment increased by 12 (3)% after BQ-123 (both p

ZD4522 - a new HMG-CoA reductase inhibitor - causes rapid and profound reductions in plasma LDL-C levels in patients with primary hypercholesterolaemia

Experimental animal data have indicated that the site of ventricular tachycardia origin and, hence, the degree of asynchronous contraction, may influence the hemodynamic tolerance during sustained ventricular tachycardia. However, data in man are scarce. We studied patients with preserved left ventricular function and absence of significant coronary artery disease. Ventricular tachycardia was simulated with rapid pacing (at 120 and 150 beats/min), performed randomly, from the right ventricular apex or the right ventricular outflow tract. Following pacing from one site, it was repeated from the alternate site. Compared to outflow tract pacing, QRS duration was significantly longer during rapid pacing from the apex. Left ventricular pressure was recorded using a micromanometer-tipped catheter. During sinus rhythm, peak systolic pressure was 142 +/- 14 mmHg; at 120 beats/min, it decreased to 109 +/- 12 mmHg during pacing from the apex and to 127 +/- 21 mmHg during pacing from the outflow tract (P = 0.008). This difference diminished at 150 beats/min (101 +/- 16 mmHg vs 112 +/- 16 mmHg, respectively, P = 0.21). During sinus rhythm end-diastolic pressure was 13 +/- 1 mmHg, which did not change significantly during pacing at 120 beats/min. During pacing at 150 beats/min, end-diastolic pressure increased to 21 +/- 3 mmHg during pacing from the apex and to 16 +/- 2 mmHg during pacing from the outflow tract (P = 0.005). Changes in first derivative of pressure and in isovolumic relaxation time constant were comparable during pacing from the two sites. Thus, it seems that tachycardias originating from the right ventricular outflow tract result in more favorable left ventricular hemodynamics, compared to those from the right ventricular apex.

I n the past few years, several novel treatment modalities have emerged as potential alternatives to the standard therapeutic approaches for a number of cardiovascular diseases. An article published in the December 2008 issue of Angiology highlights the advantages of cell therapy as a new and promising approach for the management of peripheral arterial disease (PAD). Peripheral arterial disease remains a major cause of morbidity. Despite the continuous advances in revascularization procedures and medical treatment, limb salvage and pain management are not satisfactory in patients with severe PAD. This has led to the exploration of alternative modes of treatment, such as the enhancement of new vessel formation, that is angiogenesis, by administration of vascular growth factors. Basic fibroblast growth factor (bFGF) levels are elevated in symptomatic PAD patients with critical limb ischemia. This finding, which reflects a physiologic response to limb ischemia, holds implications for the treatment of PAD. In an earlier study, it was demonstrated that plasma levels of vascular endothelial growth factor (VEGF) and bFGF may not only indicate the severity and extent of PAD but also predict the effectiveness of autologous bone marrow mononuclear cell implantation as the treatment strategy employed for the management PAD. Positive results for autologous bone marrow mononuclear cell implantation for the treatment of critical limb ischemia have also been reported by other groups. Besides the development of ‘‘new’’ therapeutic strategies for the management of ‘‘old’’ diseases, another scenario that is often seen nowadays is the report of nonclassical, ‘‘emerging’’ indications for several agents beyond and in addition to their established action. An example of such a drug is statins. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), used to treat hyperlipidemia, were shown in both in vitro and in vivo studies to exert beneficial effects beyond cholesterol lowering. Besides their established role in the management of hypercholesterolemia, statins may also have beneficial actions in other pathological conditions, namely (a) osteoporosis and osteoporosis-related bone fractures, (b) cancer, (c) solid organ transplantation, (d) cerebrovascular events (transient ischemic attack and stroke episodes), (e) various neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, (f) cardiac arrhythmias and heart failure, (g) renal diseases, (h) rheumatoid arthritis, (i) autoimmune diseases, (j) sepsis, and (k) allergic asthma. The role of statins in the management of these diseases (also called ‘‘statin pleiotropy’’) is reviewed elsewhere. The role of From the Department of Vascular Surgery (KIP) and 2nd Department of Cardiology (CP, TD, DGC, ZSK), Red Cross Hospital, Athens, Greece; Department of Clinical Biochemistry (Vascular Disease Prevention Clinic), Royal Free Hospital Campus, University College London (UCL), University of London, London, United Kingdom (DPM).

Aims: To test the hypothesis that ketanserin augments coronary collateral blood flow and decreases myocardial ischemia during balloon angioplasty. Methods and Results: Forty-four patients with single vessel disease and stable angina were studied. Collateral flow was determined during balloon inflations, based on the distal velocity time integral (13 patients) or on coronary wedge/mean arterial pressure measurements (10 patients). The 2nd and 3rd inflations lasted the same time and between them 1.5 mg intracoronary ketanserin in 10 ml normal saline was administered over 3 min. In 21 control subjects normal saline alone was given. In the flow velocity group the velocity time integral was 78.5 ± 53.1 mm during the 2nd inflation and 106.0 ± 43.2 mm during the 3rd (p < .05), while the ST deviation was 1.1 ± .7 and .7 ± .7 mm, respectively (p. < .05). In the intracoronary pressure group the CWP/MBP was .40 ± .10 during the 2nd inflation and .45 ± .11 during the 3rd (p. < .05), while the ST deviation was 1.2 ± .8 and .8 ± .8 mm respectively (p. < .05). In the controls no variables changed during the tested inflations. Conclusion: Intracoronary administration of ketanserin augments coronary collateral flow and decreases myocardial ischemia during balloon angioplasty. This could be of clinical significance in the management of acute ischemic syndromes.

The presence, cause, and clinical significance of elevated cardiac troponin I in patients with acute lower limb ischemia is yet unknown. Forty-six patients (20 men [43%]; mean age 72 +/- 10 years, range 42 to 92) with acute lower limb ischemia were enrolled in this study. Serial creatine kinase (CK), CK isoenzyme MB (CK-MB), and troponin I measurements were obtained in all consecutive patients. Peak levels were evaluated for each patient. Twenty-four patients (52%) had elevated peak troponin I levels (0.2 ng/ml) during their hospitalization. Patients were divided into 3 groups according to their peak troponin I levels: 11 patients (24%) had peak troponin I levels1 ng/ml (the high troponin I group), 13 (28%) had levels of 0.2 to 1 ng/ml (the intermediate troponin I group), and the remaining 22 (48%) had peak troponin I levels0.2 ng/ml (the low troponin I group). The peak CK levels were 10,263 +/- 16,513, 1,294 +/- 1,512, and 934 +/- 1,045 IU/ml (p = 0.04) in the 3 different troponin I subgroups, respectively, and the peak CK-MB levels were 143 +/- 170, 38 +/- 31, and 38 +/- 43, respectively (p = 0.04). Troponin I was positively correlated with CK (R = 0.35, p = 0.017) and CK-MB (R = 0.38, p = 0.009). The mean length of hospitalization was 8.3 +/- 6.2 days for the whole study group and did not vary among the 3 troponin I groups (10.5 +/- 10.9 vs 8.6 +/- 4.9 vs 7.2 +/- 4.0 days, p = 0.762). There were no differences in mortality during hospitalization among the 3 groups (4 of 11 vs 1 of 13 vs 4 of 22 patients, p = 0.22). In conclusion, patients with acute lower limb ischemia often have elevated cardiac troponin I levels. Elevated troponin I levels were not associated with the duration of hospitalization or with in-hospital mortality in this group of patients.

Objectives. This study sought to compare hormone replacement therapy (HRT), simvastatin and their combination in the management of hypercholesterolemia in postmenopausal women with coronary artery disease (CAD).Background. Lipid-lowering therapy reduces mortality in hypercholesterolemic women with CAD. In postmenopausal women HRT seems to increase survival, particularly those with ischemic heart disease, and this is partly due to changes in lipid levels.Methods. We studied 16 postmenopausal women with CAD and fasting total cholesterol

Background and hypothesis: In vitro studies have shown that atrial natriuretic peptide (ANP) causes relaxation of pre-constricted blood vessel strips and inhibits the contraction of isolated vessels in response to norepinephrine and angiotensin II. The present study examined the effects of exogenous ANP on the coronary collateral blood flow during angioplasty. Methods: We studied 15 patients undergoing elective balloon angioplasty during the second and third balloon inflations. A Doppler flow guidewire was advanced distal to the lesion and used for the estimation of coronary blood flow velocity. After the second balloon inflation, 25 ng/kg/min of ANP were administered intracoronarily for 8 min. Electrocardiogram, pressure, and flow velocity were recorded immediately before each balloon deflation. Fourteen other patients served as controls and received normal saline infusion. Results: Velocity time integral increased from 65 ± 40 to 79 ± 46 mm (p < 0.05) during the third balloon inflation, whereas ST deviation decreased from 1.3 ± 0.9 to 0.7 ± 1.0 mV (p< 0.05). These variables did not change in the control group during the two tested balloon inflations. Conclusion: Exogenous ANP augments coronary collateral blood flow and ameliorates myocardial ischemia during angioplasty.

Altered sequence of ventricular activation sequence results in marked derangements in mechanical events. In the present study, we investigated the comparative effects of atrial and AV sequential pacing on collateral blood flow during angioplasty. Twenty-eight patients with stable angina and left anterior descending artery disease undergoing balloon angioplasty were studied. Collateral flow was determined during balloon inflation from the distal flow velocity of the ipsilateral artery (17 patients) or from the increase of the maximal diastolic blood flow velocity (Vc) of the contralateral artery (11 patients). Flow measurements were made using the Doppler flow guidewire. The relative resistance in the collateral vascular bed (RR) also was estimated in the latter group of patients. After the first balloon inflation, two similar consecutive balloon inflations were done under atrial and AV sequential pacing, at a rate of 15 beats/min higher than the sinus rate, in the absence of vasoactive medication. One minute after the initiation of pacing, the second and third balloon inflations were begun and the pacing continued until the balloon inflations were completed. In the ipsilateral group, average peak velocity was 84.6 +/- 24.2 mm/2 during atrial pacing and 82.7 +/- 29.7 mm/s during AV sequential pacing (P = NS). In the contralateral group, Vc was 18% +/- 12% during atrial pacing and 17% +/- 14% during AV sequential pacing, and the RR was 4.5 +/- 4.7 and 4.9 +/- 6.4, respectively (both P = NS). The coronary wedge/mean blood pressure was similar during the two tested balloon inflations. Short-term AV sequential pacing at rest does not adversely affect collateral blood flow and resistance in patients with left anterior descending artery disease.

The effect of β-adrenergic blockade on coronary collateral blood flow has not been clarified. We examined the acute effects of β-adrenergic blockade on coronary collateral blood flow. Fifteen patients (Part A) with stable angina were studied while undergoing coronary angioplasty. According to the protocol, all patients underwent a minimum of three balloon inflations. Collateral flow velocity was determined during balloon inflations using the Doppler flow guidewire positioned distally to the lesion. The two tested balloon inflations, the second and third, were maintained for the same length of time. Between the second and third balloon inflations, 1 mg of propranolol was administered IC into the treated artery. Ten controls were studied following saline infusion. In 10 other patients (Part B), the effect of 1 mg IC propranolol on the coronary artery area distal to the lesion was studied, and five patients served as controls. In the treated group, in Part A blood pressure remained stable during the balloon inflations tested. Heart rate decreased from 79 ± 11 to 73 ± 12 beats/min (P < .05), velocity time integral from 9.6 ± 8.2 to 6.6 ± 4.1 cm (P < .05), and ST elevation from 1.3 ± .9 to .9 ± 1.0 mV (P < .05) between the second and third balloon inflations. In the controls the variables examined did not change during the balloon inflations tested. In Part B, neither propranolol nor normal saline had any significant effect on coronary artery lumen area. Thus, IC administration of β-adrenergic blockade decreases coronary collateral blood flow, and this potentially worsens the ischemic zone. However, β-adrenergic blockade ameliorates myocardial ischemia during coronary angioplasty.

17β-estradiol, administered acutely, protects ischemic myocardium in male rabbits. In the present study we investigated the effect of short-term estrogen on myocardial infarct size in oophorectomized female rabbits. We oophorectomized 24 sexually mature New Zealand white female rabbits. Twelve animals were left untreated and 12 received oral conjugated estrogens, 0.15 mg/day, for 4 weeks. At a second stage, a third group of 12 oopherectomized female rabbits was treated with intramuscular conjugated estrogens, 1 mg/day, also for 4 weeks. All rabbits underwent 30 minutes of coronary artery occlusion and 2 hours of reperfusion while on anesthesia with IV pentobarbital. Infarct and risk area were delineated by Zn-Cd fluorescent particles and tetrazolium chloride staining. The infarct size was expressed as a percentage of the risk zone (I/R %). Data are reported on 26 animals that survived the treatment period and the experiment. Heart rate, systolic, and mean blood pressure and double product did not differ between the three groups at baseline, ischemia, and reperfusion. The infarct size of the risk zone was significantly smaller in the intramuscular group compared with both the oral and the placebo group (18.5 ± 3.5% vs. 41.3 ± 9.2% and 43 ± 8.4%, respectively, P = 0.03). Conjugated estrogens, administered intramuscularly at a high dose, protect ischemic myocardium in oophorectomized female rabbits.

This study examined the effects of different atrioventricular (AV) intervals, during AV sequential pacing, on hemodynamics and coronary blood flow in individuals with normal hearts. Left anterior descending artery blood flow velocity was measured, using intracoronary Doppler, in 17 normal individuals. Five pacing tests were applied in random order for 5 min, at 15 beats/min above the sinus rate. Four tests using AV sequential pacing with AV intervals of 175, 150, 100, and 50 ms, and one using atrial pacing were applied. Mean flow velocity was 21 ± 9 cm/s, 20 ± 9 cm/s, 17 ± 7 cm/s, 17 ± 7 cm/s, and 22±10 cm/s, respectively (F = 8.87, p = .00001). The hemodynamic effects of these 5 pacing tests were assessed in 8 different normal subjects. Isovolumic relaxation time constant and left ventricular systolic pressure decreased, whereas right atrial pressure increased during AV sequential pacing with short AV intervals. Thus, during short-term AV sequential pacing at rest, coronary blood flow in a normal left anterior descending artery decreases with short AV intervals.

We investigated the effects of coronary rotational atherectomy (PTCRA) on plasma levels of endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and cyclic adenosine monophosphate (cAMP). We studied 14 patients undergoing PTCRA and compared them with 14 patients undergoing plain balloon angioplasty. Blood samples were taken from the femoral vein at baseline, after the end of the atherectomy, after the first balloon inflation, after the end of the procedure, and 4 hours later. ET-1 increased in the angioplasty group from 6.3 ± 3.2 pmol/L at baseline to 8.5 ± 3.9 pmol/L at the end of the procedure (F = 3.83, P = .02), whereas it did not change in the PTCRA group. ANP increased in the PTCRA group from 78.1 ± 15.7 pmol/L at baseline to 89.7 ± 24.0 pmol/L at the end of the procedure (F = 6.75, P = .0001), whereas it did not change in the angioplasty group. cAMP decreased in the PTCRA group, whereas it did not change in the angioplasty group. In conclusion, ET-1 increases less, ANP increases more, and cAMP decreases more during atherectomy than during plain balloon angioplasty.

Background The relative role of acute myocardial ischemia and infarction in ventricular arrhythmogenesis is incompletely understood. We compared the arrhythmia pattern after ischemia/infarction to that observed after direct myocardial necrosis without preceding ischemia in rats. Methods Coagulation necrosis was induced in Wistar rats (n=20, 280±3 g) by radiofrequency current application (for 15 s) from a 4-mm-tip ablation catheter. Myocardial infarction was induced by coronary artery ligation with (n=10) or without (n=10) reperfusion. Using 24-h telemetry recording, we examined ventricular arrhythmias, voluntary motor activity and indices of sympathetic activation. Results The coagulation-necrosis volume was 24.4%±0.6%, comparable to the infarct size in the absence of reperfusion. Acute left ventricular failure and sympathetic activation were similar in the three groups. Coagulation necrosis induced ventricular fibrillation immediately, followed by a second peak after ∼1 h. Reperfusion decreased ventricular arrhythmias, whereas a second arrhythmogenic period (between the third and the eight hour) was noted in non-reperfused infarcts (mainly monomorphic ventricular tachycardia). Conclusions Distinct arrhythmia patterns occur after myocardial infarction (with or without reperfusion) and after direct necrosis. They are not produced by differences in sympathetic activation and are likely related to the evolution of myocardial injury. The necrosis rat model may be useful in studies of arrhythmogenesis.

Transesophageal Doppler echocardiography can noninvasively evaluate the functional results of left anterior descending coronary artery angioplasty. Coronary flow reserve assessed by this technique is significantly increased only in those patients with less severe residual stenosis as detected by intravascular ultrasound, thus allowing a noninvasive assessment of the results of left anterior coronary artery angioplasty.

Although an increase in diastolic coronary flow velocity can be detected by transesophageal echocardiography 72 hours after both successful and unsuccessful left anterior coronary artery angioplasty, a significant improvement in coronary flow reserve is observed only in patients with a successful procedure. Transesophageal echocardiography-derived coronary flow reserve can identify early restenosis and thus serve as an index of the outcome of the procedure.

Chronic skeletal muscle ischemia protects the ischemic heart by preserving coronary flow and inducing arterioangiogenesis. We sought to determine the effect and the underlying molecular mechanisms of preconditioning (PreC) and postconditioning (PostC), applied in a model of chronic skeletal muscle ischemia. Male rabbits were divided into 3 series. In each series, the animals were subjected either to severe hind limb (HL) ischemia, by excision of the femoral artery, or to sham operation (SHO). After 4 weeks, all the animals underwent 30 minutes of regional heart ischemia and 3 hours reperfusion. The animals of the first series received no further intervention (HL and SHO groups), those of the second series underwent PreC (HL + PreC and SHO + PreC), and of the third series PostC (HL + PostC and SHO + PostC). Infarct size (I) and risk zones (R) were determined, and their ratio was calculated in percentage. Three additional series of experiments were performed with respective interventions up to the 10th minute of reperfusion, where sample tissue was obtained for assessment of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), glycogen synthase kinase 3β (GSK3β), p44/42, signal transducer and activator of transcription (STAT) 3, and STAT5. All groups demonstrated significantly smaller percentage of I/R compared with the SHO group (HL: 14.4% ± 3.7%, HL + PreC: 13.1% ± 1.0%, SHO + PreC: 21.3% ± 1.6%, HL + PostC: 18.0% ± 1.1%, and SHO + PostC: 24.3% ± 1.7%, P < .05 vs 35.7% ± 4.4% in SHO). The PreC and PostC did not further reduce the infarct size in HL groups. The Akt, eNOS, GSK3β, p44/42, and STAT3 were activated in all PreC or PostC groups regardless of the infarct size reduction. The STAT5 was activated only in the HL groups compared with the SHO groups. In conclusion, chronic skeletal muscle ischemia results in effective cardioprotection, which is not further enhanced with application of PreC or PostC. The Akt, eNOS, GSK3β, p44/42, and STAT3 may only be considered as indicators of the intracellular changes taking place during protection. Activation of STAT5 is possibly the end effector, which is responsible for infarct size reduction provided by chronic skeletal muscle ischemia.

This study was undertaken to investigate intracoronary production and systemic release of the atrial natriuretic factor (ANF) and cyclic-guanosine monophosphate (c-GMP) during coronary angioplasty (PTCA). three coronary blood samples were collected, through a balloon catheter, from the area distal to the lesion: before balloon inflation, at maximum inflation and 5 min later. Four additional venous samples were collected: before PTCA, and 5 min, 2 h and 24 h after the procedure. Local intracoronary c-GMP production increased from the baseline level of 7.5±0.9 pmol/ml to 11.1±1.3 pmol/ml at maximum balloon inflation (p

We investigated intracoronary cyclic-guanosine monophosphate (c-GMP) levels during percutaneous transluminal coronary angioplasty (PTCA) since experimental studies have shown the endothelial origin of c-GMP production. Intracoronary c-GMP and cyclic adenosine monophosphate (c-AMP) were measured during coronary angioplasty in 24 patients with chronic coronary artery disease. Four coronary blood samples were taken through a catheter from the coronary artery the first sample before coronary angiography and the other three from distal to coronary obstruction, as follows: before the balloon inflation, at the maximum inflation and 5 min after restoration of coronary flow. c-GMP increased from 7.9 +/- 1.0 pmol/ml and 7.5 +/- 0.9 pmol/ml before angiography and balloon inflation to 11.1 +/- 1.3 pmol/ml at the maximum inflation (P0.01), with a trend to decrease 5 min after the end of the intervention (9.5 +/- 1.0 pmol/ml, P: NS). Intracoronary c-AMP levels remained almost unchanged. Five venous samples were taken to measure c-AMP before coronary angiography, before PTCA, and 5 min, 2 h and 24 h after PTCA. c-AMP values 2 and 24 h after PTCA (17.8 +/- 1.7 pmol/ml and 17.5 +/- 1.7 pmol/ml, respectively) were lower than the highest value (22.1 +/- 2.1 pmol/ml) found 5 min after PTCA, (P0.001). c-GMP increases distal to coronary obstructive lesion during PTCA at the time of balloon inflation, while c-AMP remains unchanged. c-AMP rises in venous circulation only. PTCA stimulates the mechanism of c-GMP release, while systemic c-AMP increase seems to be related to the stress occurring during catheterisation and PTCA.

The aim of this study was to investigate if levels of circulating cyclic guanosine monophosphate (c-GMP) alter in preconditioning. Twenty-eight rabbits were divided into four groups. In vivo hearts were preconditioned, either with 5 min (group A, n = 8) or with 1 min (group B, n = 8) ischemia, followed by 10 min reperfusion, while groups C (n = 7) and D (n = 5) had no interventions. Protection was determined by subjecting groups A, B and C (but not D) to 30 min regional ischemia which was followed (including group D) by 2 h reperfusion. Seven blood samples were collected for the assessment of circulating c-GMP at different points of time. All results were expressed in pmol/ml using radio-immunoassay and the infarcted to risk area in percent using fluorescent particles and tetrazolium chloride (TTC). Circulating c-GMP increased during long ischemia only in group A (baseline value 47 +/- 4, long ischemic values 60.5 +/- 4 and 60.4 +/- 4, p < 0.05). Circulating c-GMP in group A was significantly higher in the middle of the long ischemia in comparison to the groups B, C and D (60.5 +/- 4 vs 43.9 +/- 4, 45.8 +/- 5 and 43.6 +/- 4, p < 0.05). Infarcted to risk ratio was lower in group A than in groups B and C (12.2 +/- 4 vs 29.6 +/- 6 and 34.2 +/- 6 respectively, p < 0.05). Circulating c-GMP is increased in classically preconditioned in comparison to ineffectively preconditioned hearts or to control groups. This elevation may be related to the protective effect of this phenomenon.

Transradial coronary catheterization is a world-wide growing technique. Its main complication is radial artery occlusion (RAO), which occurs in 1%-10% of the patients. We evaluate a novel technique with simultaneous compression of the ulnar artery in order to reduce the presentence of RAO.

OBJECTIVE--To determine whether an abnormal response of diastolic blood pressure during treadmill exercise stress testing correlated with the number of obstructed vessels and with left ventricular systolic function in patients with coronary artery disease. DESIGN--Diastolic blood pressure was measured invasively during exercise stress testing and coronary angiograms and left ventriculograms were obtained at rest in patients with coronary artery disease. The abnormal (> or = 15 mm Hg) diastolic blood pressure response was compared with the number of obstructed coronary arteries and with left ventricular systolic function. SETTING--Two tertiary referral centres. PATIENTS--50 consecutive patients (mean age 57 years) with coronary artery disease. MAIN OUTCOME MEASURES--The increase in diastolic blood pressure during exercise and its correlation with the appearance and disappearance of ST segment deviation, resting left ventricular systolic function, and the number of obstructed coronary arteries. RESULTS--Group 1: 10 (20%) patients (three with one, four with two, and three with three vessel coronary artery disease) (mean (SD) age 54.7 (12) years) had an abnormal diastolic blood pressure response that appeared 1.2 (0.3) min before ST segment deviation and became normal 0.9 (0.3) min after the ST segment returned to normal. Group 2: 40 (80%) patients (12 with one, 16 with two, and 12 with three vessel coronary arteries disease) (aged 56.8 (8.2) years) had a normal diastolic blood pressure response to stress testing. The ejection fraction (46.3 (5)%) and cardiac index (2.6 (0.1) 1/min/m2) in group 1 were less than in group 2 (61.6 (4.2)% and 3.8 (0.3) 1/min/m2 respectively, p < or = 0.001). The end systolic volume was greater in group 1 than in group 2: 38.7 (0.7 ml/m2 v 28.2 (2.1) ml/m2, p < or = 0.001. CONCLUSION--In patients with coronary artery disease an abnormal increase in diastolic blood pressure during exercise stress testing correlated well with left ventricular systolic function at rest but not with the number of obstructed coronary arteries. The abnormal response of diastolic blood pressure probably reflects deterioration of myocardial function.