Franco Fabbiocchi

Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality

Context Contrast-induced nephropathy (CIN) can complicate percutaneous coronary intervention (PCI). A better understanding of the relationship among contrast volume, patient characteristics, and CIN could help to reduce this complication. Contribution Of 561 patients who underwent primary PCI in the setting of ST-segment elevation myocardial infarction, 20% developed CIN, and those with CIN were more likely than those without CIN to die in hospital. Higher contrast volume and contrast ratio (volume administered/volume calculated) were associated with CIN and in-hospital death. Caution It is unclear whether the worse outcomes were due to the contrast or whether unmeasured aspects of disease severity led to both the need for more contrast and the worse outcomes. The Editors Primary percutaneous coronary intervention (PCI), defined as intervention in the culprit vessel within 12 hours after the onset of chest pain without previous thrombolytic or other clot-dissolving therapy, is the best available strategy for treatment of ST-segment elevation acute myocardial infarction (STEMI) (1). Patients having primary PCI, however, are at higher risk for contrast-induced nephropathy (CIN), although most of them do not have preprocedural renal dysfunction (2). Contrast-induced nephropathy is associated with a marked increase in in-hospital morbidity and mortality rates, which may partially thwart the survival benefit of primary PCI in patients who develop this serious renal complication (2, 3). Effective CIN prevention may further improve the clinical outcome of patients with STEMI who receive primary PCI. Potential preventive strategies include protecting the kidney from contrast- or ischemic-induced injury and limiting the amount of contrast administered. Studies of the antioxidant agent N-acetylcysteine (4) have yielded promising results for kidney protection. N-acetylcysteine has been shown to be effective in reducing CIN incidence and in improving clinical outcomes after emergency or primary PCI, particularly when administered as a high-dose intravenous bolus or with sodium bicarbonate (4, 5). Conversely, because few previous studies have reported the amount of contrast used, data on the effect of contrast volume limitation during primary PCI are lacking. Moreover, investigators disagree on the relation between the volume of contrast administered during interventional procedures and the risk for CIN. Some studies have reported no relationship, whereas others have suggested an independent correlation (614). ST-segment elevation myocardial infarction further complicates the issue. Patients with STEMI who are not undergoing primary PCI may also have acute worsening of renal function with the same prognostic implications as for CIN (15), which suggests that acute kidney injury may result from hemodynamic compromise rather than from CIN per se. In addition, primary PCI success, a major determinant of clinical outcome in patients with STEMI (1618), may require larger amounts of contrast. Thus, an optimal procedural result should be carefully weighed against risk for CIN. The association of contrast volume, as an absolute and a weight- and creatinine-adjusted value (19); CIN incidence; and clinical outcome in the setting of primary PCI remains unknown. As a result, evidence-based recommendations to guide best procedural strategies during primary PCI are still lacking. We sought to prospectively assess the possible association between contrast volume and CIN incidence and in-hospital clinical outcome in patients with STEMI who undergo primary PCI. Methods Study Population We conducted our prospective observational study at the Centro Cardiologico Monzino, University of Milan, between 1 January 2002 and 30 September 2007. We enrolled all consecutive patients with STEMI who were undergoing primary PCI. According to our institute protocol, we included patients who presented within 12 hours (18 hours for STEMI complicated by cardiogenic shock) of the onset of symptoms (characteristic pain lasting for at least 30 minutes, not responsive to nitrates, with electrocardiographic ST-segment elevation of at least 0.2 mV in 2 or more contiguous leads, or left bundle-branch block). We excluded patients receiving long-term peritoneal or hemodialysis treatment. We also excluded patients if they had cardiac surgery for emergency coronary revascularization or STEMI-related mechanical complications, died during PCI, or had been treated with an intravenous bolus of N-acetylcysteine before PCI. The Ethics Committee of the Centro Cardiologico Monzino approved the study, and all patients gave written, informed consent. PCI Procedure A 24-hour on-call interventional team performed primary PCI according to standard clinical practice by using standard guide catheters (6 French), guide wires, and balloon catheters via the femoral approach. Patients received a 5000-U bolus of heparin, followed by additional boluses during the procedure to maintain an activated clotting time longer than 300 seconds (between 200 and 250 seconds when abciximab was used). Coronary stenting was performed with standard technique. Contrast dose was left to the discretion of the interventional cardiologist. All patients received nonionic, low-osmolar contrast agents (iomeprol or iohexol). After contrast exposure, patients received isotonic (0.9%) saline intravenously at a rate of 1 mL/kg per hour for 12 hours. In patients with a left ventricular ejection fraction (LVEF) lower than 40% or overt heart failure, the hydration rate was reduced to 0.5 mL/kg per hour. Poststenting antithrombotic treatment consisted of aspirin and either clopidogrel or ticlopidine at standard dosages. Data Collection We measured serum creatinine concentration in all patients at hospital admission (before primary PCI), every day for the following 3 days, at discharge from the coronary care unit, and at hospital discharge. We estimated creatinine clearance by applying the CockcroftGault formula to the serum creatinine concentration (20). We defined preprocedural renal insufficiency as a creatinine clearance less than 1 mL/s (60 mL/min) (21). We calculated the maximum contrast dose (MCD) for each patient by using the formula proposed by Cigarroa and colleagues (19): MCD (mL) = (5body weight [kg]) divided by serum creatinine (mg/dL). From this contrast limit, we determined the contrast ratio by dividing the administered contrast amount by the calculated MCD. We left the use of -adrenergic blocking agents, angiotensin-converting enzyme inhibitors, platelet glycoprotein IIb/IIIa receptor inhibitors (abciximab), diuretics, intra-aortic balloon pump, or inotropic drug support to the discretion of the interventional and coronary care unit cardiologists, on the basis of the current standards of care recommended by published guidelines (22). During hospitalization, medications were changed as needed at the discretion of the cardiologist responsible for the patient. The primary end point of the study was the occurrence of CIN, defined as a greater than 25% increase in creatinine concentration from the baseline value in the 72 hours after primary PCI (23). In-hospital mortality rate and other major adverse clinical events were also evaluated as secondary end points. Statistical Analysis On the basis of our previous study (2), we calculated a sample size of 550 patients, assuming a 30% incidence of patients exceeding the MCD and a 10% incidence of CIN in patients with a contrast ratio less than 1. This sample size allowed 84% statistical power to assess a significantly higher ( error of 0.05) CIN incidence of 20% (odds ratio, 2) in the group with a contrast ratio greater than 1. We present continuous variables as means (SDs); we compared them by using the t test for independent samples or one-way analysis of variance, as appropriate. We compared categorical data by using the chi-square test or the Fisher exact test, as appropriate. The P values reported in Table 1 were not adjusted for multiple comparisons. Table 1. Patient and Procedure Characteristics We explored the relationship between contrast ratio and maximum percentage increase in creatinine concentration after primary PCI by using linear regression analysis. Both variables were log-transformed before analysis. We estimated predicted probabilities of CIN and mortality from the logistic models with the covariates set to the population average values. We assessed the association among contrast volume, contrast ratio, and clinical outcomes (CIN and in-hospital mortality) through logistic regression analysis. First, we included only contrast volume or contrast ratio (model 1). To adjust for potential confounders selected among recognized clinical predictors of the 2 outcomes (age, body weight, infarct location, LVEF, time to reperfusion, and baseline creatinine level), we developed 2 multivariable logistic regression models: model 2, which adjusted for the 2 major predictors (LVEF and creatinine level), and model 3, which adjusted for the 6 considered variables. Because contrast ratio is a calculated variable that includes both body weight and creatinine, we did not include those 2 variables in the models when we tested the association with contrast ratio. Thus, model 2 included LVEF and time to reperfusion, whereas model 3 included age, infarction location, LVEF, and time to reperfusion. Because of the relatively small number of events, we only considered mortality models with 2 or fewer covariates. To assess whether the effect of contrast volume on CIN differed in patients with renal insufficiency, we stratified our sample according to creatinine clearance (1 or <1 mL/s [60 or <60 mL/min]) and tested the appropriate interaction terms by using logistic regression, adjusting with model 2. All tests were 2-sided. We performed all calculations by using SAS, version 9.13 (SAS Institute, Cary, North Carolina). Role of the Funding Source The Centro Cardiologico Monz

Upward shift of the lower range of coronary flow autoregulation in hypertensive patients with hypertrophy of the left ventricle.

BackgroundAt any given perfusion pressure, coronary reserve is expressed by the difference between autoregulated and maximally vasodilated flow. In hypertension the raised coronary resistance reduces the steepness of the pressure-flow relationship at maximal vasodilatation. In the presence of cardiac hypertrophy the line of autoregulated flow becomes higher. For these reasons coronary reserve is reduced and the point at which baseline flow approaches the maximal achievable flow might be shifted to a higher perfusion pressure. Thus, any reduction below this elevated and critical value of pressure would lower the coronary flow. Methods and ResultsThe investigated patients were normotensive (controls, nine) and hypertensive with normal (group I, seven) or augmented LV mass index because of concentric LV hypertrophy (group II, eight). All had effort-induced angina and angiographically normal left epicardial branches. Flow in the great cardiac vein was measured by thermodilution in the baseline and during stepwise (5 mm Hg every 5 minutes) decrease of the coronary perfusion pressure with a titrated nitroprusside i.v. infusion; perfusion pressures of 60 mm Hg in the controls and 70 mm Hg in the hypertensives were taken as end points. Baseline flow averaged 102 ml/min in normotensives, 104 ml/min in hypertensive group I and 148 ml/min in hypertensive group II. At the end points flow was similar to baseline in the controls and group I. In group II coronary flow started to decline and myocardial 02 extraction started to slightly but significantly rise at perfusion pressures of 90-80 mm Hg; at the end point flow was reduced by 26% (p<0.01 from baseline). The perfusion patterns did not seem to be related to the changes in tension-time index and heart rate. ConclusionsThe association of high blood pressure (reduced ability of the coronary arterioles to dilate) and hypertrophy of the myocardium (augmented baseline coronary flow) may shift the point of exhaustion of coronary reserve to a higher perfusion pressure and make the myocardium vulnerable to treatment-induced relative hypertension. (Circulation 1991;83:845–853)

Microembolization during carotid artery stenting in patients with high-risk, lipid-rich plaque: A randomized trial of proximal versus distal cerebral protection

OBJECTIVES The goal of this study was to compare the rate of cerebral microembolization during carotid artery stenting (CAS) with proximal versus distal cerebral protection in patients with high-risk, lipid-rich plaque. BACKGROUND Cerebral protection with filters partially reduces the cerebral embolization rate during CAS. Proximal protection has been introduced to further decrease embolization risk. METHODS Fifty-three consecutive patients with carotid artery stenosis and lipid-rich plaque were randomized to undergo CAS with proximal protection (MO.MA system, n = 26) or distal protection with a filter (FilterWire EZ, n = 27). Microembolic signals (MES) were assessed by using transcranial Doppler during: 1) lesion wiring; 2) pre-dilation; 3) stent crossing; 4) stent deployment; 5) stent dilation; and 6) device retrieval/deflation. Diffusion-weighted magnetic resonance imaging was conducted before CAS, after 48 h, and after 30 days. RESULTS Patients in the MO.MA group had higher percentage diameter stenosis (89 ± 6% vs. 86 ± 5%, p = 0.027) and rate of ulcerated plaque (35% vs. 7.4%; p = 0.019). Compared with use of the FilterWire EZ, MO.MA significantly reduced mean MES counts (p < 0.0001) during lesion crossing (mean 18 [interquartile range (IQR): 11 to 30] vs. 2 [IQR: 0 to 4]), stent crossing (23 [IQR: 11 to 34] vs. 0 [IQR: 0 to 1]), stent deployment (30 [IQR: 9 to 35] vs. 0 [IQR: 0 to 1]), stent dilation (16 [IQR: 8 to 30] vs. 0 [IQR: 0 to 1]), and total MES (93 [IQR: 59 to 136] vs. 16 [IQR: 7 to 36]). The number of patients with MES was higher with the FilterWire EZ versus MO.MA in phases 3 to 5 (100% vs. 27%; p < 0.0001). By multivariate analysis, the type of brain protection was the only independent predictor of total MES number. No significant difference was found in the number of patients with new post-CAS embolic lesion in the MO.MA group (2 of 14, 14%) as compared with the FilterWire EZ group (9 of 21, 42.8%). CONCLUSIONS In patients with high-risk, lipid-rich plaque undergoing CAS, MO.MA led to significantly lower microembolization as assessed by using MES counts.

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.

Prevention of contrast nephropathy by furosemide with matched hydration: The MYTHOS (induced diuresis with matched hydration compared to standard hydration for contrast induced nephropathy prevention) trial

OBJECTIVES This study investigated the effect of furosemide-forced diuresis and intravenous saline infusion matched with urine output, using a novel dedicated device designed for contrast-induced nephropathy (CIN) prevention. BACKGROUND CIN is a frequent cause of acute kidney injury associated with increased morbidity and mortality. METHODS A total of 170 consecutive patients with chronic kidney disease (CKD) undergoing coronary procedures were randomized to either furosemide with matched hydration (FMH group, n = 87) or to standard intravenous isotonic saline hydration (control group; n = 83). The FMH group received an initial 250-ml intravenous bolus of normal saline over 30 min followed by an intravenous bolus (0.5 mg/kg) of furosemide. Hydration infusion rate was automatically adjusted to precisely replace the patients urine output. When a urine output rate >300 ml/h was obtained, patients underwent the coronary procedure. Matched fluid replacement was maintained during the procedure and for 4 h post-treatment. The definition of CIN was a ≥25% or ≥0.5 mg/dl rise in serum creatinine over baseline. RESULTS In the FMH group, no device- or therapy-related complications were observed. Four (4.6%) patients in the FMH group developed CIN versus 15 (18%) controls (p = 0.005). A lower incidence of cumulative in-hospital clinical complications was also observed in FMH-treated patients than in controls (8% vs. 18%; p = 0.052). CONCLUSIONS In patients with CKD undergoing coronary procedures, furosemide-induced high urine output with matched hydration significantly reduces the risk of CIN and may be associated with improved in-hospital outcome. (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention [MYTHOS]; NCT00702728).

Emergency percutaneous coronary intervention in patients with ST-elevation myocardial infarction complicated by out-of-hospital cardiac arrest: Early and medium-term outcome

BACKGROUND The role of emergency reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI) resuscitated after an out-of-hospital cardiac arrest (OHCA) has not been clearly established yet. The aim of this study was to evaluate the in-hospital and postdischarge outcomes of STEMI patients surviving OHCA and undergoing emergency angioplasty (percutaneous coronary intervention [PCI]) within an established regional network. METHODS We prospectively collected data on 2,617 consecutive patients with STEMI treated with emergency PCI in 2005; in-hospital and 6-month outcomes of 99 patients who had experienced OHCA were compared with those of 2,518 patients without OHCA. The OHCA patients also underwent a cerebral performance evaluation after 12 months. RESULTS OHCA patients were at higher clinical risk at presentation (cardiogenic shock 26% vs 5%, P < .0001). Percutaneous coronary intervention was successful in 80% of the OHCA and 89% of the non-OHCA patients (P = NS). In-hospital mortality rates were 22% and 3%, respectively (P < .0001). Independent predictors of in-hospital mortality among OHCA patients were longer delay between the call to the emergency medical system and the start of cardiopulmonary resuscitation (odds ratio [OR] 3.5, P = .03), nonshockable initial rhythms (OR 10.5, P = .002), cardiogenic shock (OR 3.05, P = .035), and a Glasgow Coma Scale score of 3 on admission (OR 2.9, P = .032). The 6-month composite rate of death, myocardial infarction, and revascularization among OHCA patients surviving the acute phase was comparable to that of non-OHCA patients (16% vs 13.9%, P = NS), and 87% of them showed a favorable neurologic recovery after 1 year. CONCLUSIONS Resuscitated OHCA patients undergoing emergency PCI for STEMI have worse clinical presentation and higher in-hospital mortality compared to those without OHCA. However, subsequent cardiac events are similar, and neurologic recovery is more favorable than reported in most previous series.

Optical coherence tomography compared with intravascular ultrasound and with angiography to guide coronary stent implantation (ILUMIEN III: OPTIMIZE PCI): a randomised controlled trial

BACKGROUND Percutaneous coronary intervention (PCI) is most commonly guided by angiography alone. Intravascular ultrasound (IVUS) guidance has been shown to reduce major adverse cardiovascular events (MACE) after PCI, principally by resulting in a larger postprocedure lumen than with angiographic guidance. Optical coherence tomography (OCT) provides higher resolution imaging than does IVUS, although findings from some studies suggest that it might lead to smaller luminal diameters after stent implantation. We sought to establish whether or not a novel OCT-based stent sizing strategy would result in a minimum stent area similar to or better than that achieved with IVUS guidance and better than that achieved with angiography guidance alone. METHODS In this randomised controlled trial, we recruited patients aged 18 years or older undergoing PCI from 29 hospitals in eight countries. Eligible patients had one or more target lesions located in a native coronary artery with a visually estimated reference vessel diameter of 2·25-3·50 mm and a length of less than 40 mm. We excluded patients with left main or ostial right coronary artery stenoses, bypass graft stenoses, chronic total occlusions, planned two-stent bifurcations, and in-stent restenosis. Participants were randomly assigned (1:1:1; with use of an interactive web-based system in block sizes of three, stratified by site) to OCT guidance, IVUS guidance, or angiography-guided stent implantation. We did OCT-guided PCI using a specific protocol to establish stent length, diameter, and expansion according to reference segment external elastic lamina measurements. All patients underwent final OCT imaging (operators in the IVUS and angiography groups were masked to the OCT images). The primary efficacy endpoint was post-PCI minimum stent area, measured by OCT at a masked independent core laboratory at completion of enrolment, in all randomly allocated participants who had primary outcome data. The primary safety endpoint was procedural MACE. We tested non-inferiority of OCT guidance to IVUS guidance (with a non-inferiority margin of 1·0 mm2), superiority of OCT guidance to angiography guidance, and superiority of OCT guidance to IVUS guidance, in a hierarchical manner. This trial is registered with ClinicalTrials.gov, number NCT02471586. FINDINGS Between May 13, 2015, and April 5, 2016, we randomly allocated 450 patients (158 [35%] to OCT, 146 [32%] to IVUS, and 146 [32%] to angiography), with 415 final OCT acquisitions analysed for the primary endpoint (140 [34%] in the OCT group, 135 [33%] in the IVUS group, and 140 [34%] in the angiography group). The final median minimum stent area was 5·79 mm2 (IQR 4·54-7·34) with OCT guidance, 5·89 mm2 (4·67-7·80) with IVUS guidance, and 5·49 mm2 (4·39-6·59) with angiography guidance. OCT guidance was non-inferior to IVUS guidance (one-sided 97·5% lower CI -0·70 mm2; p=0·001), but not superior (p=0·42). OCT guidance was also not superior to angiography guidance (p=0·12). We noted procedural MACE in four (3%) of 158 patients in the OCT group, one (1%) of 146 in the IVUS group, and one (1%) of 146 in the angiography group (OCT vs IVUS p=0·37; OCT vs angiography p=0·37). INTERPRETATION OCT-guided PCI using a specific reference segment external elastic lamina-based stent optimisation strategy was safe and resulted in similar minimum stent area to that of IVUS-guided PCI. These data warrant a large-scale randomised trial to establish whether or not OCT guidance results in superior clinical outcomes to angiography guidance. FUNDING St Jude Medical.

Clinical and angiographic outcome after coronary arterial stenting with the Carbostent

The Carbostent is a new balloon-expandable, stainless steel, tubular stent with innovative multicellular design and unique turbastratic carbon coating (Carbofilm). This open nonrandomized 2-center study assesses the immediate and long-term clinical and angiographic outcomes after Carbostent implantation in patients with native coronary artery disease. The Carbostent was implanted in 112 patients with 132 de novo lesions. Most patients (55%) had unstable angina, and 38% of lesions were type B2-C. The mean lesion length was 12.5 +/- 7.0 mm, and 29% of lesions were > 15 mm in length. No stent deployment failure occurred, as well as acute or sub-acute stent thrombosis. The 6-month event-free survival was 84 +/- 4%. One patient with a stented right coronary artery and no restenosis at the angiographic follow-up died after 6 months of fatal infarction due to abrupt closure of a nontarget vessel. In-hospital non-Q-wave myocardial infarction occurred in 1 patient, and 11 patients had repeat target lesion revascularization (target lesion revascularization rate 10%). The 6-month angiographic follow-up was obtained in 108 patients (96%) (127 lesions). Angiographic restenosis rate was 11%. The loss index was 0.29 +/- 0.28. The results of this study indicate a potential benefit of Carbostent for the prevention of stent thrombosis and restenosis in these relatively high-risk patients. A larger trial is being planned to confirm these promising results.

Optical coherence tomography imaging during percutaneous coronary intervention impacts physician decision-making: ILUMIEN I study

Aims ILUMIEN I is the largest prospective, non-randomized, observational study of percutaneous coronary intervention (PCI) procedural practice in patients undergoing intra-procedural pre- and post-PCI fractional flow reserve (FFR) and optical coherence tomography (OCT). We report on the impact of OCT on physician decision-making and the association with post-PCI FFR values and early clinical events. Methods and results Optical coherence tomography and documentary FFR were performed pre- and post-PCI in 418 patients (with 467 stenoses) with stable or unstable angina or NSTEMI. Based on pre-PCI OCT, the procedure was altered in 55% of patients (57% of all stenoses) by selecting different stent lengths (shorter in 25%, longer in 43%). After clinically satisfactory stent implantation using angiographic guidance, post-PCI FFR and OCT were repeated. Optical coherence tomography abnormalities deemed unsatisfactory by the implanting physician were identified: 14.5% malapposition, 7.6% under-expansion, 2.7% edge dissection and prompted further stent optimization based on OCT in 25% of patients (27% of all stenoses) using additional in-stent post-dilatation (81%, 101/124) or placement of 20 new stents (12%). Optimization subgroups were identified post hoc: stent placement without reaction to OCT findings (n = 137), change in PCI planning by pre-PCI OCT (n = 165), post-PCI optimization based on post-PCI OCT (n = 41), change in PCI planning, and post-PCI optimization based on OCT (n = 65). Post-PCI FFR values were significantly different (P = 0.003) between optimization groups (lower in cases with pre- and post-PCI reaction to OCT) but no longer different after post-PCI stent optimization. MACE events at 30 days were low: death 0.25%, MI 7.7%, repeat PCI 1.7%, and stent thrombosis 0.25%. Conclusion Physician decision-making was affected by OCT imaging prior to PCI in 57% and post-PCI in 27% of all cases. ClinicalTrials.gov Identifier NCT01663896, Observational Study of Optical Coherence Tomography (OCT) in Patients Undergoing Fractional Flow Reserve (FFR) and Percutaneous Coronary Intervention (ILUMIEN I).

Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest

Syndrome X is characterized by an abnormal vasomotility of coronary microvessels. It is unknown whether the presence of an ischemic-like pattern in the electrocardiogram at rest (T-wave inversion) reflects a more severe vasomotion disturbance. Changes in coronary sinus flow (thermodilution) and epicardial vessel diameter (quantitative angiography) during adrenergic activation were measured with a standard cold pressor test in patients with syndrome X whose electrocardiogram at rest was normal (group 1: 17 patients) or showed stable, symmetrically inverted T waves (group 2: 22 patients). Cold pressor test increased mean blood pressure and rate-pressure product to a similar extent in both groups, increased coronary sinus flow in group 1 (88 +/- 29 to 119 +/- 36 ml/min; p less than 0.05) and not in group 2 (109 +/- 37 vs 104 +/- 36 ml/min; p = not significant), and decreased coronary resistance in group 1 (1.38 +/- 0.42 to 1.19 +/- 0.38 mm Hg/ml/min; p less than 0.05) and augmented it in group 2 (1.06 +/- 0.32 to 1.28 +/- 0.43 mm Hg/ml/min; p less than 0.02). During cold stimulus, the proximal and middle segments of epicardial arteries showed negligible changes in their lumen, whereas the distal segment dilated in group 1 (1.81 +/- 0.27 to 2.01 +/- 0.32 mm; p less than 0.05) and constricted in group 2 (1.82 +/- 0.12 to 1.62 +/- 0.20 mm; p less than 0.05). Differences in coronary hemodynamic and angiographic responses between the groups were statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)