Advances in pharmacotherapy for cardiac amyloidosis.

INTRODUCTION: Amyloidosis is a group of progressive and devastating disorders resulting from extracellular deposition of misfolded proteins into tissues. When deposition of fibrils occurs in cardiac tissues, this systemic disease can lead to a very poor prognosis. Systemic amyloidosis can be acquired [light chain (AL) amyloidosis; AA amyloidosis], or hereditary [transthyretin (ATTR) amyloidosis]. Cardiac disease in amyloidosis is usually secondary to a systemic disease. The diagnosis of cardiac involvement is often delayed and yields an adverse prognosis. AREAS COVERED: in this review, the authors report current literature on advances in pharmacotherapy for cardiac amyloidosis, mainly focused on AL and ATTR amyloidosis treatment. EXPERT OPINION: Most pharmacological trials in amyloidosis patients, both AL and TTR, are directed to study the effects of drugs on polyneuropathy. However, since cardiac involvement carries a prominent negative survival impact in amyloidosis patients, future research should be more focused on amyloidosis cardiomyopathy as primary endpoint. Additionally, in AL amyloidosis therapies are mainly derived from experience on multiple myeloma treatment. In this specific setting, possible future research could particularly focus on immunotherapeutic agents able to optimize the standard chemotherapy results and, thus, allowing a larger population of patients to be treated by bone marrow stem cell transplantation.

Pharmacotherapy for the treatment of obstructive hypertrophic cardiomyopathy.

Introduction: Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases and represents a leading cause of sudden cardiac death as well as a prevalent cause of heart failure and stroke. HCM is characterized by a very complex pathophysiology, consisting of heterogeneous clinical manifestations and natural history. Left ventricular outflow tract (LVOT) obstruction has been considered the most knowable feature of HCM since the initial clinical descriptions of the disease.Areas covered: In this review, the authors discuss the most recent reports on the pharmacological treatment of obstructive HCM, mainly based on three different levels of intervention: control of symptoms, cardiac metabolism modulation and disease-modifying approaches, including genetic preventive therapies.Expert opinion: There are presently limited data supporting pharmacological interventions for this complex disease. However, an improved understanding of HCM pathophysiology will allow the development of novel treatment options. Two important key messages are to further study drugs with negative but limited previous results and to design new and larger trials for those molecules that have already produced positive results in HCM, especially for pressure gradients and symptoms control.

Effects of short-term manipulation of serum FFA concentrations on left ventricular energy metabolism and function in patients with heart failure: no association with circulating bio-markers of inflammation.

BACKGROUND AND AIMS: We wanted to assess the effects of short-term changes in serum free fatty acids (FFAs) on left ventricular (LV) energy metabolism and function in patients with heart failure and whether they correlated with circulating markers of inflammation. METHODS AND RESULTS: LV function and phosphocreatine (PCr)/ATP ratio were assessed using MR imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) in 11 men with chronic heart failure in two experimental conditions 7 days apart. Study 1: MRI and 31P-MRS were performed before and 3-4 h after i.v. bolus + continuous heparin infusion titrated to achieve a serum FFA concentration of 1.20 mM. Study 2: The same protocol was performed before and after the oral administration of acipimox titrated to achieve a serum FFA concentration of 0.20 mM. Serum concentrations of IL6, TNF-α, PAI-1, resistin, visfatin and leptin were simultaneously assessed. Serum glucose and insulin concentrations were not different between studies. The PCr/ATP ratio (percent change from baseline: +6.0 ± 16.9 and -16.6 ± 16.1 % in Study 1 and Study 2, respectively; p = 0.005) and the LV ejection fraction (-1.5 ± 4.0 and -6.9 ± 6.3 % in Study 1 and Study 2, respectively; p = 0.044) were reduced during low FFA when compared to high FFA. Serum resistin was higher during Study 1 than in Study 2 (p < 0.05 repeated measures ANOVA); meanwhile, the other adipocytokines were not different. CONCLUSION: FFA deprivation, but not excess, impaired LV energy metabolism and function within hours. Cautions should be used when sudden iatrogenic modulation of energy substrates may take place in vulnerable patients.

Erectile dysfunction in heart failure patients: a critical reappraisal.

Heart failure (HF) is a complex clinical syndrome with a constantly increasing incidence and prevalence in western countries. Total absence of sexual activity is registered in 30% of HF patients. Moreover, HF-induced reduction in exercise tolerance, side effects of HF medications and the coexistence of shared risk factors between HF and sexual dysfunction may further aggravate the sexual health of HF patients. The purpose of this review is to examine the pathophysiological mechanisms behind the association of erectile dysfunction (ED) and HF, the potential therapeutic approaches and the eventual indications for sexual activity in HF patients. Medline and Cochrane Library search was performed from January 1970 through October 2012 to retrieve relevant papers outlining the association between ED and HF. Many evidences have outlined a tight association between ED and HF pathophysiological standpoint. Shared risk factors, common pathogenic traits and epidemiologic association represent some of the links between these conditions. Erectile dysfunction has been recognized as an earlier predictor of cardiovascular events; moreover, HF itself may cause and/or worsen ED because of its particular feature and co-morbidities. Furthermore, some cardiovascular drugs may contribute to impaired erectile function. In stable patients with stable HF, sexual activity is generally not contraindicated but it should be encouraged, as a form of moderate-intensity physical exertion. An effective treatment of ED in HF patients should be founded on the correction of reversible risk factors, on the choice of cardiovascular drugs with the lowest effect upon patient's erectile function, and on the use of phosphodiesterase-5-inhibitors. Physicians should be aware of the close relation between HF and ED and of the related clinical and therapeutic implications, in order to improve patients quality of life and clinical outcome.

NYHA Class II subgrouping: correlation with left ventricular dysfunction questionnaire (LVD-36) and ejection fraction.

AIM: NYHA classification divides into four classes. Although subjective and lacking of standardization, NYHA class II is in clinical practice often further subgrouped in IIA and IIB, where IIA class can be defined as dyspnea after running or climbing ≥ 2 ramps of stairs, and IIB class as dyspnea after fast walking or climbing 2 ramps of stairs. Validation of NYHA IIA and IIB sub-grouping was performed with left ventricular dysfunction questionnaire (LVD-36) results and echocardiographic left ventricular ejection fraction. METHODS: The study includes a total of 127 patients with both systolic and diastolic heart failure (mean age 65 ± 17, range 38-85 years). Sixteen patients were in NYHA class I, 81 patients in NYHA class II (45 in class IIA and 36 in class IIB) and 30 in class III. RESULTS: In class IIA patients' mean age was 64 ± 9 years, LVD-36 score 31.79 ± 14.06, EF 43 ± 10% (P = ns, P<0.001 and P=ns, respectively, vs. class I patients). In class IIB patients' mean age was 67 ± 10 years, LVD-36 score 48.90 ± 15.51, EF 39 ± 12% (P = ns, P < 0.0001 and P = ns, respectively, vs. IIA patients). In class III patients' mean age was 65 ± 11 years, LVD-36 score 65.17 ± 16.35, EF 32.77 ± 12.91% (P = ns, P < 0.01 and P = ns, respectively, compared with class IIB). CONCLUSION: NYHA class II sub-grouping appears an accurate method of classification and could represent a further useful tool in monitoring functional capacity of heart failure patients. NYHA class II sub-grouping correlates well with patients functional impairment and can therefore be implemented as an accurate method to better characterize heart failure patients.

Inhibition of free fatty acids metabolism as a therapeutic target in patients with heart failure.

Recent studies have evidenced that alterations of cardiac metabolism can be present in several cardiac syndromes. In heart failure, wasting of subcutaneous fat and skeletal muscle is relatively common and suggests an increased utilisation of non-carbohydrate substrates for energy production. In fact, fasting blood ketone bodies as well as fat oxidation during exercise have been shown to be increased in patients with heart failure. This metabolic shift determines a reduction of myocardial oxygen consumption efficiency. A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilisation by the heart. To date, the most effective metabolic treatments include several pharmacological agents that directly inhibit fatty acid oxidation. Clinical studies have shown that these agents can substantially increase the ischaemic threshold in patients with effort angina. However, the results of current research is also supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and towards glucose metabolism could be an effective adjunctive treatment in patients with heart failure, in terms of left ventricular function and glucose metabolism improvement. In fact, these agents have also been shown to improve overall glucose metabolism in diabetic patients with left ventricular dysfunction. In this paper, the recent literature on the beneficial therapeutic effects of modulation of cardiac metabolic substrates utilisation in patients with heart failure is reviewed and discussed.

[Cardiovascular and hormonal strain in waste collection workers employed in Amsa SpA, municipality of Milan, in permanent day and night work]. / Valutazione dello strain cardiovascolare ed ormonale in operatori ecologici del comune di Milano in turno fisso diurno e notturno.

UNLABELLED: Aim of the study is to explore in shiftworkers: a) blood pressure and hormonal variations; b) dyslipidemia and blood glucose levels; c) insulin resistence syndrome. We have assessed 48 male workers employes in Amsa SpA, a large municipal enterprise in charge of street cleaning and domestic waste collection, in permanent day and night work as hand sweepers, motor sweepers and delivery tricar drivers. 24 of those workers (daily and nightly) were normotensive and 24 were hypertensive. Our medical checks were: physical examination: BMI; laboratory findings (blood): glucose, total cholesterol, triglycerides, endothelin, insulin, FFA, HOMA S, HOMA B, HOMA R; assay of salivary cortisol and urinary cortisol in 24 h; 24 h pressure monitoring. RESULTS: Nightly hypertensive: increased consumption in wine and coffee, weight and BMI, total cholesterol and FFA and endothelin. Nightly normotensive: increased consumption in cigarettes and salivary cortisol. Daily hypertensive: increased total cholesterol; 24 h pressure monitoring showed more pronounced variations of pressure in night workers both normotensive and hypertensive in working time. CONCLUSIONS: Night shiftwork looks like more stressfull than day shiftwork. Insuline resistance isn't noticed in all four groups.

Left ventricular hypertrophy and QT interval in obesity and in hypertension: effects of weight loss and of normalisation of blood pressure.

BACKGROUND: Left ventricular hypertrophy (LVH) and prolonged QT interval at ECG (QTc) are common in both obesity and arterial hypertension (AH), and are risk factors for cardiovascular disease and sudden death. METHODS: We compared the frequencies of LVH (ECG criteria) and QTc in obese-AH (n=41), in normotensive obese (n=75), in lean-AH (n=30), and in lean controls (n=68) comparable for age and sex; in obese patients, LVH and QTc were evaluated under basal conditions and 1 y later, that is, after a significant weight loss induced by bariatric surgery. RESULTS: LVH was more frequent, and QTc was longer, in obese-AH, in normotensive obese, and in lean-AH than in lean controls; after weight loss, frequency of LVH decreased in obese subjects becoming normotensive (n=87), not in obese subjects remaining hypertensive (n=29), while QTc decreased in all obese subjects. CONCLUSION: Weight loss can effectively reduce QTc; when concomitant AH disappears, weight loss can also reduce the prevalence of LVH. In obese patients remaining hypertensive, aggressive pharmacological treatment is therefore indicated to correct LVH.

Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy.

BACKGROUND: Trimetazidine (TMZ) has been shown to partially inhibit free fatty acid oxidation by shifting substrate utilization from fatty acid to glucose. The aim of this study was to assess the effects of TMZ in patients with diabetes and ischemic cardiomyopathy. METHODS: Sixteen patients with diabetes and ischemic hypokinetic cardiomyopathy (all males) on conventional therapy were randomized to receive either placebo or TMZ (20 mg 3 times per day), each arm lasting 15 days, and then again to receive either placebo or TMZ for 2 additional 6-month periods, according to a double-blind, crossover design. At the end of each period, all patients underwent exercise testing, 2-dimensional echocardiography, and hyperinsulinemic/euglycemic clamp. Among the others, New York Heart Association class, ejection fraction, exercise time, fasting blood glucose, end-clamp M value (index of total body glucose disposal) and endothelin-1 levels were evaluated. RESULTS: Both in the short and long term (completed by 13 patients), on TMZ compared to placebo, ejection fraction (47 +/- 7 vs 41 +/- 9 and 45 +/- 8 vs 36 +/- 8%, P <.001 for both) and M value (4.0 +/- 1.8 vs 3.3 +/- 1.6, P =.003, and 3.5 +/- 1.5 vs 2.7 +/- 1.6 mg/kg body weight/min, P <.01) increased, while fasting blood glucose (121 +/- 30 vs 136 +/- 40, P =.02 and 125 +/- 36 vs 140 +/- 43, P =.19) and endothelin-1 (8.8 +/- 3.8 vs 10.9 +/- 3.8, P <.001 and 6.2 +/- 2.4 vs 9.2 +/- 4.3 pg/mL, P =.03) decreased. In the short term, 10 patients decreased 1 class on the NYHA scale during treatment with TMZ (P =.019 vs placebo). Eight patients decreased 1 NYHA class while on long-term TMZ treatment, while on placebo 1 patient increased 1 NYHA class and none improved (P =.018 vs placebo). CONCLUSIONS: In a short series of patients with diabetes and ischemic cardiomyopathy, TMZ improved left ventricular function, symptoms, glucose metabolism, and endothelial function. Shifting energy substrate preference away from fatty acid metabolism and toward glucose metabolism by TMZ appears an effective adjunctive treatment in patients with diabetes with postischemic cardiomyopathy.

Minimal myocardial damage after tricyclic neuroleptic overdose - a case report.

A great number of acute, severe self-poisoning cases are due to tricyclic neuroleptic overdose. These drugs may induce several effects on the myocardium, mainly related to arrhythmias and electrical conduction and excitation abnormalities. These abnormalities are particularly evident after massive ingestion of these drugs for suicidal purposes. More recently, abnormal ventricular repolarization, in association with QRS widening, that mimics an acute ischemic event has been reported. However, these transient ECG abnormalities have never been associated with organic cardiac alterations. We report the case of a young woman who - according to ECG, enzyme release, and echocardiography - developed transient acute myocardial ischemia and minimal myocardial damage following self-poisoning with promazine hydrochloride. To our knowledge, this is the first case of documented minimal myocardial damage after tricyclic drugs overdose.

Time course and determinants of left ventricular function recovery after primary angioplasty in patients with acute myocardial infarction.

OBJECTIVES: We sought to evaluate the importance of time in relation to treatment, time course and determinants of recovery of left ventricular (LV) function in patients with acute myocardial infarction (AMI) undergoing primary percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Myocardial salvage has been shown to be dependent on the time elapsed from the onset of AMI to reperfusion. METHODS: Left ventricular function was evaluated at hospital admission, after angioplasty, at 24 h and 6 months by both echocardiography and angiography and at 1, 7, 30, 90 and 180 days by echocardiography in 101 consecutive patients. RESULTS: Patients were allocated to three groups according to interval between symptom onset and angioplasty: <2 h (group A), 2 to 4 h (group B) and >4 h (group C). Patients in groups A and B showed a progressive improvement of LV function between day 7 and day 90, which became statistically significant at day 30 (p < 0.01). No LV function changes were noted in group C patients. Thrombolysis In Myocardial Infarction (TIMI) flow grade <3 at 24 h was not associated with any significant change in LV volume and function during the six-month follow-up period. Restenosis, when associated with TIMI flow grade 3 in the infarct-related vessel, did not influence LV function. Flow grade <3 of the infarct-related artery was not associated with any improvement of cardiac events independently from the time to treatment at the initial procedure. CONCLUSIONS: Patients undergoing primary PTCA for AMI have a good recovery of LV function if TIMI flow grade 3 is restored within 4 h. Coronary angioplasty limits further remodeling of the LV in patients treated after 4 h.

Influence of treatment delay on long-term left ventricular function in patients with acute myocardial infarction successfully treated with primary angioplasty.

BACKGROUND: Myocardial salvage has been shown to be dependent on the time elapsed from the onset of acute myocardial infarction (AMI) to reperfusion. The aim of this study was to evaluate the importance of time to reperfusion for left ventricular function recovery after primary angioplasty (percutaneous transluminal coronary angioplasty [PTCA]) for AMI. METHODS: Ninety-five patients undergoing long-term successful PTCA for AMI were studied. Echocardiography was performed before and 3, 7, 30, 90, and 180 days after PTCA. End-diastolic volume index (EDVI) and end-systolic volume index (ESVI), ejection fraction, and left ventricular wall motion score index (WMSI) were evaluated. RESULTS: Patients were divided into group A, 23 patients reperfused within 2 hours; group B, 32 patients reperfused between 2 and 4 hours; group C, 22 patients reperfused between 4 and 6 hours; and group D, 18 patients reperfused between 6 and 12 hours. Both EDVI and ESVI were reduced in groups A and B at 90 days. Groups C and D did not show any changes of EDVI and ESVI at any stage throughout the study. Ejection fraction improved only in groups A and B at 30, 90, and 180 days. At study entry, WMSI was similar in all groups. After 7 days, in group A and in group B, WMSI was improved, no changes were observed in group C, and a mild deterioration was observed in group D at 3 and 7 days. Subsequent evaluations showed progressive improvement of WMSI in all groups. CONCLUSIONS: Myocardial salvage is achieved only in patients revascularized within 4 hours from AMI onset. However, revascularization after 6 hours may be worthwhile by preventing ventricular remodeling.

Diagnosing coronary artery disease in patients with hypertension: a resolved dilemma?

Patients with hypertension frequently complain of chest pain and exhibit ischemic-like ST segment changes on exercise electrocardiogram. However, the specificity of such changes for predicting significant coronary artery disease is very low, since these patients often exhibit a normal coronary angiogram. Several alternative non-invasive tests have been proposed and, recently, the relative performance of the available techniques has been systematically assessed. The purpose of this article is to review the relevant literature on the diagnostic tests employed in the clinical setting. Recent evidence suggests that stress echocardiography yields a better diagnostic accuracy than perfusion scintigraphy in identifying significant epicardial coronary artery disease in patients with hypertension. The low specificity of myocardial scintigraphy probably relates to the fact that this method traces perfusion abnormalities, not necessarily caused by epicardial coronary artery disease, possibly due to microvascular disease, and not axiomatically causing obvious wall motion abnormalities.

Detrimental effects of acute heparin administration on ischemic threshold in patients with coronary artery disease.

BACKGROUND: Recent studies have indicated that heparin administration might decrease endothelial nitric oxide production. The aim of this study was to investigate the effect of heparin on ischemic threshold. METHODS: Eighteen patients with a positive exercise test and proven coronary artery disease were submitted to a randomized, placebo-controlled trial using i.v. 0.9% NaCl as placebo and i.v. heparin (5,000 IU bolus + 1,000 IU/h). After both saline and heparin bolus, the infusion was started and, after 10 min, the exercise test was performed. Blood samples for nitric oxide metabolites and free fatty acid determinations were taken before, at peak exercise, and at ECG recovery. RESULTS: As compared to placebo, heparin significantly decreased time to 1 mm ST segment depression (241 +/- 160 vs 303 +/- 175 s, p = 0.003) and prolonged recovery (573 +/- 177 vs 441 +/- 195 s, p = 0.003), while exercise duration was similar. Accordingly, rate-pressure product at 1 mm ST segment depression was lower after heparin, while it was similar at peak exercise. No significant differences were found for plasma nitric oxide metabolite levels. Conversely, free fatty acid levels were higher after heparin throughout the study in all patients. The increase in free fatty acids was not correlated with the difference in rate-pressure product at 1 mm ST segment depression between placebo and heparin (r = 0.34, p = NS). CONCLUSIONS: In patients with stable coronary artery disease, heparin significantly decreased exercise ischemic threshold. The lower rate-pressure product at 1 mm ST segment depression during heparin, compared to placebo, suggests an impairment of coronary blood flow, which does not seem to be mediated by decreased nitric oxide production/release. The increased free fatty acid release, on the other hand, might contribute to the detrimental effect of heparin on exercise-induced ischemia, but the lack of a correlation with changes in ischemic threshold suggests that other, still unknown, factors are involved.

[The primary and secondary prevention of ischemic cardiopathy]. / Prevenzione primaria e secondaria della cardiopatia ischemica.

The aim of this paper was to summarize the most important clinical issues on coronary artery disease prevention, in order to provide the best advice to cardiologists, and facilitate their work on primary and secondary prevention. Although in recent years the knowledge of the beneficial effects of major risk factor modification has been increasing, most physicians still concentrate only on patients with overt coronary artery disease. Many high-risk individuals are not adequately advised and treated, whilst a great effort should be made by national institutions and individual doctors to implement primary prevention schemes. Indeed, the potential for preventive measures is greatest in high-risk groups. Specific international task forces have issued official recommendations on the prevention of coronary heart disease in clinical practice, which have been intended to encourage the development and revision of national guidelines on coronary prevention. The challenge for cardiologists in the year 2000 is to realize the potential for coronary prevention in all patients, and to contribute to reduce the enormous socio-economic burden of cardiovascular disease.

Relationship between endothelin-1 concentration and metabolic alterations typical of the insulin resistance syndrome.

The purpose of the study was to examine the relationship between the endothelin-1 (ET-1) concentration and the metabolic variables characteristic of the insulin resistance syndrome ([IRS] hyperinsulinemia, insulin resistance, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, visceral obesity, and glycemic abnormalities). The measurement of circulating ET-1 is a well-recognized marker of endothelial atherosclerotic and cardiovascular disease. Two hundred subjects were divided into 3 groups. Group 1 included 50 subjects with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) with IRS. Group 2 included 50 subjects with IGT or NIDDM without IRS. Group 3 included 100 normal subjects as controls. ET-1 levels were higher in group 1 versus groups 2 and 3 in women (11.2 +/- 0.7 v 7.9 +/- 0.5 and 6.6 +/- 0.4 pg/mL, P < .01) and men (10.1 +/- 0.6 v 6.5 +/- 0.8 and 7.2 +/- 0.3 pg/mL, P < .01). No differences were found between groups 2 and 3. With simple regression analysis, ET-1 levels significantly correlated with insulin, glycosylated hemoglobin, body weight, waist to hip ratio, and triglyceride values. However, with multiple regression analysis, only triglycerides (P < .009) and glycosylated hemoglobin (P < .001) remained independently correlated with ET-1. In conclusion, this cross-sectional study indicates that glycosylated hemoglobin and triglycerides are independently correlated with ET-1 levels in patients with IRS.

Enoximone echocardiography for predicting recovery of left ventricular dysfunction after revascularization : a novel test for detecting myocardial viability.

BACKGROUND: The possibility that enoximone, a nonglycoside, noncatechol, positive inotropic agent, in combination with 2-dimensional echocardiography may predict recovery of myocardial dysfunction after revascularization has not been yet evaluated. METHODS AND RESULTS: Forty-five patients with chronic coronary artery disease and left ventricular dysfunction underwent dobutamine (DE, 5 to 10 microg. kg(-1). min(-1)) and enoximone (EE, 1.5 mg/kg, over 10 minutes) echocardiography. Myocardial wall motion was scored from 1 (normal) to 4 (dyskinesia): an asynergic segment was considered to have contractile enhancement when the score decreased by >/=1 grade. Of 478 asynergic segments, 216 (45%) exhibited functional recovery after revascularization. Dobutamine- and enoximone-induced contractile enhancement was observed in 41% and 46% of segments, respectively. Compared with DE, EE had higher sensitivity (88% versus 79%, P<0.01) and negative predictive value (90% versus 84%, P<0.05) in predicting functional recovery. The specificity (89% versus 90%) and positive predictive value (87% for both EE and DE) were similar. Concordant interpretation of EE and DE findings was found in 85% (406 of 478) of affected segments. Prerevascularization coronary angiography showed that stenosis severity of vessels supplying areas which only improved with enoximone was significantly greater (89.9%) than that of vessels (77.7%) supplying areas that responded to both agents (P<0.02). Both dobutamine and enoximone increased heart rate (16% and 10%, respectively), whereas enoximone did not cause changes in systolic blood pressure that increased by 14% with dobutamine. CONCLUSIONS: Enoximone echocardiography provides a novel and reliable approach for the prediction of functional recovery after revascularization. Compared with dobutamine echocardiography, the test yields higher sensitivity and induces lesser hemodynamic alterations.

Endothelial and metabolic characteristics of patients with angina and angiographically normal coronary arteries: comparison with subjects with insulin resistance syndrome and normal controls.

OBJECTIVES: This study was performed to characterize the endothelial and metabolic alterations of patients with angina and angiographically normal coronary arteries ("cardiac" syndrome X [CSX]) compared with subjects with insulin resistance syndrome ("metabolic" syndrome X [MSX]) and normal controls. BACKGROUND: Previous studies have found high endothelin-1 levels, impaired endothelium-dependent vasodilation and insulin resistance in patients with angina pectoris and angiographically normal coronary arteries. On the other hand, subjects with insulin resistance syndrome have shown high endothelin-1 levels. METHODS: Thirty-five subjects were studied: 13 patients with angina pectoris and angiographically normal coronary arteries (CSX group); 9 subjects with insulin resistance syndrome (MSX group) and 13 normal controls. All subjects received an acute intravenous bolus of insulin (0.1 U/kg) combined with a euglycemic clamp and forearm indirect calorimetry. Endothelin-1 levels, nitrite/nitrate (NOx) levels, end products of nitric oxide metabolism, glucose infusion rates (index of insulin sensitivity) and their incremental areas (deltaAUCs [area under curves]) were measured during this period. RESULTS: Basal endothelin-1 levels were higher in CSX and MSX groups than in normal controls (8.19 +/- 0.46 and 6.97 +/- 0.88 vs. 3.67 +/- 0.99 pg/ml; p < 0.01), while basal NOx levels were significantly higher in MSX group than in CSX and normal controls (36.5 +/- 4.0 vs. 24.2 +/- 3.3 and 26.8 +/- 3.2 mol/liter, p < 0.05). After insulin administration, the deltaAUCs of NOx (p < 0.05) were lower in CSX group than in MSX and normal controls, and the deltaAUCs of endothelin-1 were lower in group CSX than in normal controls. Glucose infusion rate was significantly lower in CSX and MSx groups than in normal controls (p < 0.01), suggesting that in both CSX and MSX groups insulin resistance is present. A positive correlation was found between the deltaAUCs of nitric oxide and the AUCs of glucose infusion rate. CONCLUSIONS: Blunted nitric oxide and endothelin responsiveness to intravenously infused insulin is a typical feature of patients with angina pectoris and angiographically normal coronary arteries and may contribute to the microvascular dysfunction observed in these subjects.