Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide

STUDY OBJECTIVES: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH. DESIGN: Single center, case series, pharmacohemodynamic study. SETTING: Cardiac catheterization laboratory of a tertiary care academic teaching hospital. PATIENTS: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH. INTERVENTIONS: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization. MEASUREMENTS AND RESULTS: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function. CONCLUSIONS: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.     

枸橼酸西地那非治疗心脏手术后肺动脉高压的临床研究

目的研究枸橼酸西地那非对心脏手术后重度肺动脉高压的影响。方法自2002年9月至2005年1月共使用枸橼酸西地那非治疗心脏手术后重度肺动脉高压共27例,其中10例小儿,17例成人。男17例,女10例,年龄1～63岁(平均37岁),体重6～67kg(平均40kg)。所有病例均在术前行超声心动图检查确诊为重度肺动脉高压。27例患者中14例先天性心脏病,其中9例为室间隔缺损;1例为右室双出口;1例为房间隔缺损;1例为完全性肺静脉异位引流;1例为动脉导管未闭;1例为三房心。上述先心病患者均行心内畸形矫治术。另外13例为风湿性心脏病,其中11例重度二尖瓣狭窄,2例重度二尖瓣关闭不全,13例患者均合并有三尖瓣关闭不全,均行二尖瓣人工瓣膜置换术、三尖瓣整形术;其中2例合并有主动脉瓣病变同期行主动脉瓣人工瓣膜置换术,1例因合并有冠心病同期行冠状动脉旁路移植术。所有病例术后均予持续镇静和镇痛,保持适度的过度通气,维持轻度呼碱状态,同时积极地纠正各种水、电解质紊乱及代谢性酸中毒。给予多巴胺3～10μg.kg-1.min-1,米力农0.5μg.kg-1.min-1强心治疗,NO吸入(10～70)×10-6及前列腺素E1(PGE1)10～40ng.kg-1.min-1维持肺血管扩张,降低肺动脉压力。经上述处理后,27例患者术后72小时内尚反复出现肺动脉压升高,血氧饱和度、血氧分压下降,肺氧合功能下降,其中7例患者出现肺动脉高压危象。给予高浓度吸氧,增加NO吸入浓度及PGE1用量,肺动脉压仍无明显下降,肺氧合功能无进一步改善,即给予枸橼酸西地那非(辉瑞制药公司,商品名万艾可),1～2mg/kg,每8小时一次。观察患者肺动脉压、动脉血压、血氧饱和度、动脉氧分压、动脉二氧化碳分压、吸氧浓度、NO吸入浓度的变化。结果服用枸橼酸西地那非1小时以后,25例患者血氧饱和度、血氧分压渐上升,肺动脉压开始下降,体循环血压稳定或稍增高。1～2天后,吸氧浓度下降,渐降低或停用NO吸入,以及减量使用PGE1,肺动脉压基本稳定,无进一步上升,肺氧合功能改善,并顺利停用呼吸机。使用枸橼酸西地那非期间无一例患者再次出现肺动脉高压危象,血流动力学平稳。25例患者顺利出院,2例患者因术后低心排综合征而出现多器官功能衰竭死亡。结论枸橼酸西地那非是一种新型的、高选择性降低心脏手术后严重肺动脉高压的药物。     

Hemodynamic and coronary vasodilative action of two nitroglycerin oral spray formulations

Summary This study compared glycerol trinitrate (NTG) oral spray in a new hydrophilic formulation with a reference aerosol in a lipophilic base with respect to the time to onset of action on hemodynamics and on the coronary vasomotor tone. Differences in the profile of action between the two spray formulations were assessed in two groups of ten patients each. In each of the two groups the patients were randomly assigned to receive 0.8 mg of aerosolized NTG in either the hydrophilic or lipophilic base in double-blind fashion. The patients of group A had stable, exercise-induced angina pectoris, in whom responses to the sprays were evaluated under resting conditions. The patients of group B were suspicious of vasospastic or mixed form of angina pectoris, in whom the effects of the sprays were studied under diagnostic ergonovine provocation. The onset and extent of action of the sprays were assessed by serial measurements of hemodynamic parameters and repeat quantitative coronary angiography.The two formulation of NTG oral spray had a comparably potent coronary vasodilator effect in patients under resting conditions and under ergonovine provocation. As far as hemodynamic action is concerned, the new hydrophilic spray exerted its hemodynamic effect more rapidly than the lipophilic spray. Thus, the new NTG oral spray promises to afford therapeutic advantages for the relief of anginal attacks as well as hemodynamic unloading in congestive heart failure and acute pulmonary hypertension.     

Pulmonary hemodynamic responses to brain natriuretic peptide and sildenafil in patients with pulmonary arterial hypertension

STUDY OBJECTIVES: Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition. DESIGN: Open-label study. SETTING: Medical ICUs of three tertiary care hospitals in New England. PATIENTS: Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH. INTERVENTIONS: Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil. RESULTS: iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (+/- SE) was greater than after 1 h of sildenafil alone (44.6 +/- 3.8 to 40.6 +/- 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 +/- 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance. CONCLUSIONS: A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.     

Hemodynamic effects of molsidomine at rest and during submaximal and maximal exercise in patients with coronary artery disease limited by exertional angina pectoris

To analyze the mechanisms of action of molsidomine, a new antianginal drug, 10 patients with coronary artery disease and exertional angina pectoris were studied. Hemodynamic measurements were made at rest, during submaximal exercise and during angina-limited exercise before and 1 hour after intravenous administration of 2 mg of molsidomine. When angina pectoris was prevented after the drug was given (6 of 10 patients), the exercise intensity was increased until the recurrence of angina (3 patients) or until exhaustion (3 patients), and hemodynamic data were recorded at this higher exercise capacity. At rest and during submaximal exercise, molsidomine increased heart rate and decreased cardiac output and mean systemic and pulmonary arterial pressures. The prevention of angina pectoris was attended by lower mean systemic and pulmonary arterial pressures and pressure-rate product; cardiac output and heart rate were unchanged. The greater exercise capacity (+26 percent) after molsidomine was attended by increases in maximal cardiac output (+19 percent) and in arteriovenous oxygen difference (+6 percent); the maximal pressure-rate product was unchanged and systemic vascular resistance was lower. The mechanisms of action of molsidomine are very similar to those of nitrates and imply a decrease in venous and arterial tone. Molsidomine deserves further study in patients with angina or congestive heart failure.     

Findings on routine right heart catheterization in patients with suspected coronary artery disease

Whether catheterization of the right heart should be performed routinely in all patients undergoing coronary angiography for assessment of coronary artery disease is controversial. To objectively assess the utility of routine right heart catheterization, hemodynamic data from 2,178 patients studied for angina having no signs, symptoms, or history of congestive heart failure were analyzed retrospectively. The salient results are as follows: 0.9% patients had unsuspected mitral valve gradients greater than or equal to 5 mm Hg; 0.4% had occult left-to-right shunts; 1% had pulmonary hypertension (pulmonary artery systolic pressure greater than or equal to 40 mm Hg) not attributable to an elevated mean pulmonary capillary wedge pressure (PCWP); 4.8% had PCWP greater than or equal to 18 mm Hg; 6% had cardiac indexes less than or equal to 2.0 L/min/m2, suggesting subclinical left ventricular failure. Overall, 14.5% of patients had at least one abnormal right-sided hemodynamic variable revealed by right heart catheterization. The frequency of abnormalities increased with increasing Canadian Cardiovascular Society grade of angina. Ten percent of grade 1, 14% of grade 2, 15% of grade 3, and 19% of patient 4 patients had at least one abnormality (phi 2 test, p less than or equal to 0.005). It is concluded that the right heart catheterization adds an important dimension to the diagnosis and treatment of patients undergoing coronary angiography for assessment of coronary artery disease and might significantly influence subsequent patient management.     

Medical treatment of patients with stable angina pectoris referred for coronary angiography: failure of treatment or failure to treat

BACKGROUND: Patients referred for elective coronary arteriography because of stable angina pectoris frequently do not receive appropriate medical therapy prior to arteriography. Persistence of symptoms due to lack of appropriate therapy may influence the decision to catheterize and the treatment chosen following catheterization. HYPOTHESIS: The present study evaluates whether patients with stable angina pectoris referred for cardiac catheterization received optimal therapy prior to the procedure. We also evaluated whether medical therapy was optimized as a result of the hospitalization for catheterization. METHODS: We evaluated prospectively the adequacy of medical therapy in 333 consecutive patients undergoing elective coronary arteriography. Of these, 160 had stable angina pectoris as their main problem and constituted the study group. RESULTS: Mean duration of angina was 7.5 +/- 6.3 months. Canadian Cardiovascular Society angina grade 1 was present in 20, grade 2 in 77, grade 3 or 4 in 63 patients. Arteriography showed a > or = 50% coronary stenosis in 141 of 160 patients. Aspirin was used by 96%, and 86% received at least one drug aimed at relieving anginal symptoms: beta blockers in 69%, calcium blockers in 30%, and long-acting nitrates in 29%. Antianginal drugs and drugs aimed at treating risk factors were usually taken at a low, subtherapeutic dosage. Only 35 of 110 patients taking beta blockers had a resting heart rate of <60/min. Following catheterization, 88 of 141 patients with coronary stenosis of > or = 50% underwent percutanous intervention and 5 had urgent surgery. Optimization of treatment was advised in only 7 of 48 patients for whom medical therapy or elective surgery was recommended. CONCLUSION: Patients with stable angina pectoris are frequently referred for cardiac catheterization without making a serious attempt to control their symptoms by medical therapy. Risk factors are undertreated. With proper pharmacotherapy, many patients might have become asymptomatic and have chosen not to undergo catheterization and subsequent percutaneous interventions.     

Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension

STUDY OBJECTIVES: Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects of sildenafil have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients. STUDY DESIGN: We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oral sildenafil to test acute hemodynamic response during right-heart catheterization. RESULTS: iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01). CONCLUSION: All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol.     

冠状动脉痉挛诱发心律失常的临床特点及治疗效果

目的探讨冠状动脉痉挛（CAS）诱发心律失常的临床特点及治疗效果。方法选择1998年7月至2008年12月期间入住本院的16例CAS患者,CAS的诊断根据病史和症状,结合标准12导联心电图、动态心电图及冠状动脉造影等检查确定。结果16例患者CAS发作时伴有心绞痛和心电图ST段抬高。全部病例均合并缓慢性和／或快速性心律失常,其中缓慢性心律失常6例,二、三度房室阻滞5例,窦性静止1例;快速性心律失常12例,其中持续性室性心动过速（室速）和心室颤动（室颤）5例,非持续性室速5例,室性早搏2例。冠状动脉造影显示,4例冠状动脉完全正常,4例冠状动脉狭窄等于或超过50％,其余8例冠状动脉狭窄均≤45％。全部病例均接受了大剂量钙拮抗剂和硝酸酯类的联合抗血管痉挛治疗。冠状动脉有明显狭窄的4例患者接受了介入治疗。除1例患者死亡外,其余患者平均随访（52．3±18．9）个月,无心绞痛及晕厥发作。结论有或无冠状动脉病变的CAS均可诱发缓慢性和／或快速性室性心律失常;除针对冠状动脉基础病变治疗外,地尔硫革和硝酸酯类等联合抗痉挛治疗是主要的治疗措施。     

Pharmacology and therapeutic effects of nicorandil

Summary Nicorandil, a nicotinamide derivative, is an orally efficacious antianginal drug possessing a nitrate moiety in its chemical structure. This drug is an effective and welltolerated treatment for various types of angina pectoris. Its general efficacy is similar to that of nitrates, with several unique effects on the cardiovascular system. Nicorandil causes sustained dilation of both the arterial resistance and conductive vessels, thus markedly dilating the coronary artery and increasing coronary blood flow. In addition, nicorandil, unlike nitroglycerin or isosorbide dinitrate, possesses little hemodynamic effect on heart rate, blood pressure, or cardiac contractility with clinical doses yielding antianginal effects. The mechanism causing coronary vasodilation has not been completely clarified but appears to be associated partly with increases in c-GMP, as well as the hyperpolarization of the smooth muscle membrane.Nicorandil, in single oral doses of 10–30 mg, has been shown to be effective in chronic stable angina, as assessed objectively by increases in exercise duration and/or the time to onset of ST-segment depression during treadmill exercise. In open studies and controlled efficacy evaluations, nicorandil in daily oral doses of 15–40 mg demonstrated significant effectiveness in the treatment of various types of angina pectoris. Headaches due to vasodilation may occur, and some side effects occurred in 5.1–34% of patients receiving nicorandil, but were generally minor in nature. There was not depressant effect on atrioventricular conduction, which occurs frequently in patients treated with calcium antagonists of the verapamil and diltiazem type. Nicrorandil may be effective even in patients with rest and effort angina who do not respond to combination therapy with calcium antagonists and oral nitrates. Thus, nicorandil appears to be a valuable addition to the arsenal of antianginal drugs due to its low incidence of serious side effects.     

Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure

This study sought to evaluate the utility of sildenafil in assessing pulmonary artery reactivity in left-sided cardiac failure and secondary pulmonary hypertension (PH). Fourteen consecutive patients with heart failure were studied, with oral doses of either sildenafil 25 mg (n = 8) or 50 mg (n = 6) every 8 hours for 20% decreases in pulmonary artery pressures. There was also a 20% reduction of the pulmonary vascular resistance/systemic vascular resistance ratio, indicating relative pulmonary artery selectivity. Compared with sildenafil 25 mg, sildenafil 50 mg demonstrated greater reductions of pulmonary pressures. Oral sildenafil is safe and effective for the evaluation of PH reactivity in heart failure.     

Effects of nicorandil on left ventricular hemodynamics and volume at rest and during exercise-induced angina pectoris

The hemodynamic effects of nicorandil (20 mg) were compared with placebo in a double-blind study of 20 patients with angiographically proved coronary artery disease at rest before and 7, 15, 30 and 60 minutes after oral dosing. The impact of the drug on left ventricular (LV) hemodynamics and volume during exercise-induced angina was determined by repeating exercise 60 minutes after drug administration, at the same work load that reliably induced angina during control predrug exercise.

At rest, nicorandil reduced all components of systemic arterial pressure without change in cardiac or stroke volume indexes or heart rate. Pulmonary artery occluded pressure was reduced without change in LV ejection fraction or systemic vascular resistance index. Effects were evident at 7 minutes and peaked at 30 minutes with attenuation at 60 minutes. Compared with control supine bicycle exercise, the drug (at 60 minutes) reduced mean systemic arterial pressure and LV filling pressure without change in cardiac stroke volume indexes and heart rate. There was a smaller increase in LV ejection fraction.

These data suggested greatest impact on LV function during exercise when substantial decreases in filling pressure occurred at maintained cardiac pumping indexes.     

Angiographic occurrence and clinical correlates of intraluminal coronary artery thrombus: role of unstable angina

The importance of intraluminal coronary artery thrombus in acute myocardial infarction is now recognized. Coronary thrombi, however, may be important in ischemic syndromes other than infarction. The coronary angiograms of 268 consecutive patients undergoing diagnostic angiography were prospectively examined for intracoronary thrombus and form the basis of this study. Of these patients, 29 (11%) (25 men and 4 women) met the criteria for coronary artery thrombus. Of the 29 patients with thrombus, 24 (83%) had unstable angina before angiography. The five remaining patients with thrombus had had a transmural myocardial infarction 3 to 18 months before cardiac catheterization. In 21 patients, the thrombus was distal to a significant stenosis; in 8 it was proximal to or at the site of a significant stenosis. Coronary artery thrombus was identified in 24 (35%) of 67 patients with unstable angina compared with only 5 (2.5%) of 201 patients with stable angina (p less than 0.0001).     

Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.     

Clinical management of patients with coronary syndromes and negative fractional flow reserve findings

AIMS: New interventional techniques to diagnose coronary artery stenosis, such as calculation of myocardial fractional flow reserve (FFR) with a guidewire and pressure transducer, provide a functional assessment of coronary lesions. The present study was designed to investigate the occurrence of cardiac events in patients with coronary syndromes and negative FFR findings in moderately severe coronary stenosis in order to determine the usefulness of this technique in predicting coronary events during follow-up for problems commonly encountered in clinical practice. A further objective was to evaluate the safety of deferring angioplasty in patients with a negative FFR result. METHODS: We studied 43 patients with 44 moderately severe coronary artery stenoses on angiography and FFR > or = 0.75. Mean age of the patients was 58 +/- 11.4 years. The indications for coronary angiography included recent unstable angina in 24 (55.8%) patients, recent acute myocardial infarction in 10 (23.2%) patients, 5 (11.6%) patients with a coronary stent who had symptoms of uncertain cause, and stable angina in 4 (9.3%) patients. RESULTS: During a mean follow-up period of 10.7 +/- 5.9 months, clinical events (unstable angina) occurred in five patients. In three patients, the initially investigated artery was involved, and in the two patients who required coronary revascularization, unstable angina was related with an artery different from the one studied initially. CONCLUSIONS: Patients with recent coronary syndromes and negative FFR findings in moderately severe coronary stenosis were unlikely to have cardiac events during a 10-month follow-up period. Our findings suggest that FFR is a potentially useful indicator of the likelihood of cardiac events and thus represents a useful aid in clinical decision-making in the hemodynamics laboratory. This diagnostic technique also is potentially useful in identifying patients for whom angioplasty can be safely deferred.     

Antiischemic and hemodynamic effects of an oral single dose of 150 mg of the phosphodiesterase inhibitor enoximone in patients with coronary artery disease—relation to plasma concentration

The hemodynamic and antiischemic effects of a 150-mg single oral dose of the PDE inhibitor enoximone were correlated with the plasma levels of enoximone and its sulfoxide metabolite. Twenty-one patients with angiographically documented coronary artery disease were investigated by exercise testing 1 and 2 hours after drug administration. The control group consisted of 15 patients with proven coronary artery disease and stable reproducible angina pectoris on exercise. The enoximone group included 14 responders with therapeutic plasma concentrations 2 hours after drug intake and significantly reduced mean pulmonary artery pressures on exercise (from 42.4 +/- 8.6 to 30.9 +/- 11.2 mmHg, p less than 0.05). Compared to basal exercise values, responders showed a reduced ST-segment depression by 1 hour after drug intake (2.1 +/- 1.2 vs. 1.3 +/- 3 mm, p less than 0.05) and minimal values after 2 hours (0.9 +/- 1.0 mm, p less than 0.01) at comparable workloads. There were no significant changes in heart rate, blood pressure, cardiac output, and systemic vascular resistance. No significant improvement in the hemodynamic parameters and ST-segment depression was found in nonresponders with plasma concentrations below 100 ng/ml and 500 mg/ml for enoximone and its metabolite, respectively. In summary, oral administration of enoximone in patients with coronary artery disease led to favorable acute hemodynamic and antiischemic effects at sufficiently high plasma levels of enoximone and its sulfoxide metabolite.     

Effects of thrombolytic therapy in unstable angina: clinical and angiographic results

The incidence of intracoronary thrombus and the effects of thrombolytic therapy were studied in 41 patients with unstable angina. All patients underwent coronary angiography 2 to 69 h (mean 19) after their last attack of chest pain. Immediately after angiography, 21 patients received intracoronary streptokinase (250,000 IU in 45 min) and were retrospectively analyzed. Twenty patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) (100 mg in 3 h) and were involved in a prospective study. Eleven of the 21 patients from the streptokinase group and 11 of the 20 patients from the rt-PA group showed a decrease in the severity of the coronary stenosis on repeat angiography 1 day later. A decrease in coronary obstruction was primarily observed in 10 of 13 patients with a complete stenosis and in 6 of 9 patients with a subtotal stenosis and markedly diminished coronary flow. Improvement in coronary anatomy was not determined by the clinical characteristics of the patients. Twenty-eight of the 41 patients had angiographic evidence of intracoronary thrombus formation before and 16 had such evidence after thrombolytic treatment. Nine patients developed a small increase in serum cardiac enzymes before or during treatment. Ischemic symptoms and the incidence of surgical or angioplastic intervention were not different in patients with or without a reduction in coronary artery stenosis after fibrinolytic therapy. These observations suggest a high incidence of coronary thrombosis in patients with unstable angina. The data do not permit assessment of the clinical therapeutic efficacy of thrombolytic therapy. Better risk stratification and placebo-controlled prospective studies are required to obtain information on the risk/benefit ratio of such therapy in unstable angina.     

Coronary flow limitation during the development of ischemia: Effect of atrial pacing in patients with left anterior descending coronary artery disease

Atrial pacing-induced tachycardia causes increased myocardial oxygen demand and leads to the development of angina in patients with significant coronary arterial narrowing, when the ability to augment coronary flow is limited. This study evaluated the response of coronary flow in a single coronary bed as that bed was rendered ischemic by progressive increases in oxygen demand. Thermodilution measurements of great cardiac vein flow, representing the efflux from the territory of the left anterior descending coronary artery, were obtained in 20 patients as heart rate was increased by incremental atrial pacing until the maximal heart rate was reached or angina developed. Ten of the 20 patients had no significant coronary narrowing on angiography, and 10 had a lesion obstructing more than 50 percent of the diameter of the left anterior descending coronary artery but no other significant coronary narrowing. No significant difference was found between the two groups in resting heart rate, aortic pressure, left ventricular end-diastolic pressure or great cardiac vein flow. With each increment in heart rate throughout the pacing test, the patients without significant coronary stenosis showed a steady increase in great cardiac vein flow. During all submaximal pacing increments, the increase in great cardiac vein flow per increment in heart rate was similar in those with and without significant stenosis (mean ± standard deviation 1.05 ± 0.48 ml/beat versus 0.79 ± 0.31 ml/beat, respectively). However, over the final pacing increment, the patients with coronary stenosis had no increase in great cardiac vein flow, whereas those without disease continued to have increased flow (Δ = 0.10 ± 0.19 ml/beat versus 1.3 ± 0.69 ml/beat, respectively, p < 0.001). This flow limitation phenomenon was observed in all 10 patients with coronary stenosis and was accompanied by angina or S-T segment changes, or both, in all 10. This striking difference in coronary flow patterns between patients with and without significant left anterior descending coronary artery disease may prove useful in (1) further studies of the pathophysiology and therapy of myocardial ischemia in human beings, and (2) clinical evaluation of the hemodynamic importance of left anterior descending coronary arterial lesions in selected patients.     

Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris.

AIMS: Serum levels of neopterin, an immune modulator secreted by activated macrophages, are elevated in patients with acute coronary syndromes compared with stable angina patients and control subjects. In unstable angina, serum neopterin levels correlate with the presence of vulnerable coronary stenosis, multiple complex coronary lesions, and patient outcome. The present study assessed the prognostic significance of raised serum neopterin concentrations in patients with stable angina pectoris. METHODS AND RESULTS: We carried out a 1-year follow-up prospective study in 297 patients with chronic stable chest pain undergoing diagnostic coronary angiography. The primary study endpoint was the composite of non-fatal myocardial infarction, unstable angina, and cardiac death. Fifty-one patients (17.2%) had adverse coronary events during follow-up. Mean serum neopterin levels were significantly higher in patients with events compared with those without (P=0.02). On multiple regression analysis, neopterin levels (P=0.021), severity of coronary artery disease (P=0.009), and a history of previous myocardial infarction (P=0.001) were independent predictors of adverse events. CONCLUSIONS: Serum neopterin is an independent predictor of major adverse coronary events in patients with chronic stable angina pectoris. This marker of macrophage activation may be useful for risk stratification in patients with chronic stable angina.     

Oral Nitrates: More Than Symptomatic Therapy in Coronary Artery Disease?

The predominant venodilator properties of the nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the nitrates to replenish the deficient endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in patients with coronary heart disease and also to inhibit platelet aggregation. In stable angina pectoris, the antianginal and anti- ischemic effects of oral nitrates are well established. Continuous administration of nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral nitrates without provocation of anginal attacks during periods of low nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release isosorbide-5-mononitrate in patients with stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of myocardial ischemia. In unstable angina pectoris, nitrates rapidly relieve chest pain and ameliorate the electrocardiographic signs of myocardial ischemia. In patients with acute myocardial infarction, early treatment with nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic heart failure, oral nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral nitrates reduced infarct size and morbidity and mortality in patients with acute myocardial infarction. In the ISIS 4 post-infarction study, isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of nitrates with an angiotensin-converting enzyme (ACE) inhibitor reduced mortality risks by 17% in patients with acute myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with nitrates for control of rest angina, myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label nitrates in the control groups may have diluted the true beneficial effects of nitrates in both studies. Taken together, these many studies with oral nitrate treatment in coronary heart disease and heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to coronary artery disease.