Heart failure with reduced, mildly reduced, and preserved ejection fraction: outcomes and predictors of prognosis.

INTRODUCTION: Recently, a stratification of the heart failure (HF) phenotypes, which classifies HF into 3 subtypes based on ejection fraction, has been introduced. Before that, clinical trials and registries have been mainly devoted to HF with reduced ejection fraction (HFrEF). As a result, data on long­term survival trends for individual HF phenotypes are scarce. OBJECTIVES: The study aimed to evaluate survival according to the HF phenotype and to identify predictors of mortality. PATIENTS AND METHODS: Patients hospitalized for HF in our referral center between January 2014 and May 2019 were included in the analysis. HF phenotyping was based on EF: reduced (HFrEF with EF <40%), mildly reduced (HFmrEF with EF = 40%-49%), and preserved (HFpEF with EF ≥50%). RESULTS: Of 2601 patients included in the study, 1608 individuals (62%) presented with HFrEF, 331 patients with HFmrEF (13%), and 662 patients with HFpEF (25%). The median follow­up was 2.43 years (interquartile range, 1.56-3.49). The risk of death was 61% higher in HFrEF than in HFpEF (P <0.001), while in HFmrEF and HFpEF it was similar. Survival rates at 1 and 5 years in HFrEF, HFmrEF, and HFpEF were 81%, 84%, 84%, and 47%, 61%, and 59%, respectively. The HF phenotypes differed in most of the parameters that affect prognosis. Only the use of inotropes, which was linked to an increased risk of death, and the use of angiotensin­converting enzyme inhibitors, which reduced this risk, were independent of the HF phenotype. CONCLUSIONS: Survival in HFrEF is worse as compared with HFmrEF and HFpEF, where it is similar. The HF phenotypes differ in most of the parameters that affect survival.

L-arginine and Its Derivatives Correlate with Exercise Capacity in Patients with Advanced Heart Failure.

Methylated arginine metabolites interrupt nitric oxide synthesis, which can result in endothelium dysfunction and inadequate vasodilation. Since little is known about the dynamics of arginine derivatives in patients with heart failure (HF) during physical exercise, we aimed to determine this as well as its impact on the patient outcomes. Fifty-one patients with HF (left ventricle ejection fraction-LVEF ≤ 35%, mean 21.7 ± 5.4%) underwent the cardiopulmonary exercise test (CPET). Plasma concentrations of L-arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were measured before and directly after CPET. All patients were followed for a mean of 23.5 ± 12.6 months. The combined endpoint was: any death, urgent heart transplantation, or urgent LVAD implantation. L-arginine concentrations increased significantly after CPET (p = 0.02), when ADMA (p = 0.01) and SDMA (p = 0.0005) decreased. The parameters of better exercise capacity were positively correlated with post-CPET concentration of L-arginine and inversely with post-CPET changes in ADMA, SDMA, and baseline and post-CPET SDMA concentrations. Baseline and post-CPET SDMA concentrations increased the risk of endpoint occurrence (HR 1.02, 95% CI 1.009-1.03, p = 0.04 and HR 1.02, 95% CI 1.01-1.03, p = 0.02, respectively). In conclusion, in patients with HF, extensive exercise is accompanied by changes in arginine derivatives that can reflect endothelium function. These observations may contribute to the explanation of the pathophysiology of exercise intolerance in HF.

Epidemiology and clinical characteristics of hospitalized patients with heart failure with reduced, mildly reduced, and preserved ejection fraction.

INTRODUCTION: There is still little information regarding a detailed description and predictors of different subtypes of heart failure (HF) in the Polish population. OBJECTIVES: This study sought to characterize the differences between hospitalized patients with HF divided into HF with preserved ejection fraction (HFpEF; EF ≥50%), mildly reduced EF (HFmrEF; EF 40%-49%), and reduced EF (HFrEF; EF <40%), and to identify factors related to each HF subtype. PATIENTS AND METHODS: Patients from the hospital database whose hospitalization was coded as HF­related between 2014 and 2019 were included in the analysis. RESULTS: A total of 2601 patients were included, of whom 62% had HFrEF, 13% had HFmrEF, and 25% had HFpEF. The patients with HFpEF, as compared with those with HFrEF and HFmrEF, were older (70.5 vs 61.6 vs 66.5 years, P <0.001), less often male (44% vs 68.3% vs 81.3%, P <0.001), and less likely to have an ischemic etiology of HF (19.3% vs 49.8% vs 34.4%, P <0.001) but they were more likely to have hypertension (87.3% vs 78.2% vs 78.2%, P <0.001), atrial fibrillation (64.5% vs 55.6% vs 59.5%, P <0.001), cancer (32.2% vs 19.6% vs 28.7%; P <0.001), and anemia (25.5% vs 15.9% vs 20.5%, P <0.001). Of 3 multivariable models, the one predicting HFpEF was the strongest (P <0.001, area under the curve, 0.79), and included age, sex, aortic stenosis, hypertension, anemia, cancer, thyroid abnormality, atrial fibrillation, longer history of HF, ischemic etiology, coronary artery disease, diabetes mellitus, and liver failure. CONCLUSIONS: HFrEF and HFpEF differed significantly in terms of baseline characteristics, while HFmrEF was in the middle of the HF spectrum, tending to be a mixture of HFpEF and HFrEF characteristics.

Long term outcome of heart failure patients disqualified from heart transplantation.

BACKGROUND: The prognosis of patients with advanced heart failure is unfavourable. However, little is known about the survival of patients referred for heart transplantation but finally disqualified from transplantation due to contraindications. This study aimed to evaluate the prognosis of patients' disqualified from heart transplantation. METHODS: It was a retrospective study based on medical records of patients disqualified from heart transplantation. RESULTS: One hundred and fifty-one patients were included and 94 deaths were recorded during long-term follow-up (range 0.02-10.1 years). The survival rate at 5 years was 25%. The mean age of the studied population was 57.7 years and the majority of patients were males, 87.4%. The ischaemic aetiology (66.2%) was the most dominant aetiology of heart failure. In the Cox regression model, supervision by the specialist cardiology centre (HR 0.61;p = 0.04) and pharmacotherapy with beta-blockers (HR = 0.47;p = 0.02) positively influenced the prognosis. On the contrary, well-known heart failure risk factors like a renal failure (HR 1.59;p = 0.049), pulmonary hypertension (HR 1.55;p = 0.046), liver failure (HR 2.65;p = 0.02) were negative predictors of outcome. By Kaplan-Meier analysis, patients with other than pulmonary hypertension causes of disqualification from heart transplantation had a better survival rate, p = 0.047. CONCLUSIONS: The prognosis of patients disqualified from heart transplantation is unfavourable. However, some of the patients experience relatively long survival. Therefore, careful clinical assessment and identification of factors influencing prognosis may improve adequate patients' qualifications for heart transplantation.

Accurate Noninvasive Assessment of Myocardial Iron Load in Advanced Heart Failure Patients.

BACKGROUND: Heart failure patients presenting with iron deficiency can benefit from systemic iron supplementation; however, there is the potential for iron overload to occur, which can seriously damage the heart. Therefore, myocardial iron (M-Iron) content should be precisely balanced, especially in already failing hearts. Unfortunately, the assessment of M-Iron via repeated heart biopsies or magnetic resonance imaging is unrealistic, and alternative serum markers must be found. This study is aimed at assessing M-Iron in patients with advanced heart failure (HF) and its association with a range of serum markers of iron metabolism. METHODS: Left ventricle (LV) myocardial biopsies and serum samples were collected from 33 consecutive HF patients (25 males) with LV dysfunction (LV ejection fraction 22 (11) %; NT-proBNP 5464 (3308) pg/ml) during heart transplantation. Myocardial ferritin (M-FR) and soluble transferrin receptor (M-sTfR1) were assessed by ELISA, and M-Iron was determined by Instrumental Neutron Activation Analysis in LV biopsies. Nonfailing hearts (n = 11) were used as control/reference tissue. Concentrations of serum iron-related proteins (FR and sTfR1) were assessed. RESULTS: LV M-Iron load was reduced in all HF patients and negatively associated with M-FR (r = -0.37, p = 0.05). Of the serum markers, sTfR1/logFR correlated with (r = -0.42; p = 0.04) and predicted (in a step-wise analysis, R 2 = 0.18; p = 0.04) LV M-Iron. LV M-Iron load (µg/g) can be calculated using the following formula: 210.24-22.869 × sTfR1/logFR. CONCLUSIONS: The sTfR1/logFR ratio can be used to predict LV M-Iron levels. Therefore, serum FR and sTfR1 levels could be used to indirectly assess LV M-Iron, thereby increasing the safety of iron repletion therapy in HF patients.

Fluctuations in circulating endothelial progenitor cell levels and acute cardiac graft rejection.

INTRODUCTION: Endothelial progenitor cells (EPCs) in nontransplant settings have reparative properties. However, their role in heart transplantation (HT) is not well defined. OBJECTIVES: The aim of this study was to prospectively evaluate changes in EPC levels in relation to post­HT rejection. PATIENTS AND METHODS: EPC levels were measured in 27 HT recipients for 6 months after HT. Acute cellular rejection (ACR) or antibody­mediated rejection (AMR) were assessed by right ventricular endomyocardial biopsy. RESULTS: ACR and AMR were observed in 7 (25.9%) and 6 (22.2%) patients, respectively. The ACR status at 1 month post­HT did not differ with respect to EPC immediately post­HT. At 1 month post­HT in patients without ACR or AMR, EPC levels were significantly reduced compared with the measurements immediately post­HT (P <0.001). On further follow­up, EPC levels were similar regardless of the rejection events. Nonetheless, greater changes (coefficient of variation) in EPClog (logarithmic transformation) were associated with the risk of AMR or ACR compared with those without any rejection event (median [lower-upper quartile], 15 [13-18] vs 8 [5-13]; P = 0.02 and 22 [14-26] vs 8 [5-13]; P = 0.01, respectively). The receiver operating characteristic curve showed that the coefficient of variation of EPClog of 12 was the optimal cutoff value for the prediction of rejection (area under the curve = 0.85). Higher levels were associated with greater risk of ACR or AMR (P <0.005). CONCLUSIONS: Early reduction of EPC levels was related to a lower risk of ACR or AMR. Greater changes of EPC­levels during follow­up were associated with a significantly higher risk of rejection.

Prognostic value of novel biomarkers compared with detailed biochemical evaluation in patients with heart failure.

INTRODUCTION: The assessment of prognosis is crucial for the clinical management of patients with heart failure (HF). OBJECTIVES: The aim of the study was to evaluate the usefulness of novel biomarkers for the assessment of prognosis in patients with HF, compared with a detailed assessment based on routine laboratory tests. PATIENTS AND METHODS: The study included 179 patients with HF. In all patients, routine laboratory tests were performed and selected biomarkers were measured (N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, growth hormone, myeloperoxidase, metaloproteinase 9, procollagen type III, soluble toll like receptor 2, insulin growth factor, and neutrophil gelatinase-associated lipocain). The primary endpoint was death or urgent heart transplantation, while the secondary endpoints encompassed primary endpoints plus cardioverter intervention or hospitalization for HF. RESULTS: The mean age of the study group was 52.5 years (91% were men). Most patients had advanced HF. During a 6-month follow-up, 21 primary endpoints and 63 secondary endpoints were recorded. A multiple regression analysis showed that of all laboratory variables and biomarkers, only uric acid and sodium were independent predictors of primary endpoints, and only estimated glomerular filtration rate had a predictive value for secondary endpoints. None of the biomarkers were a significant prognostic factor in the study population. CONCLUSIONS: Biomarkers do not outweigh the value of standard laboratory tests. Routine laboratory workup allows to assess multiorgan damage and provides the most significant prognostic data. Biochemical tests should remain the gold standard for the assessment of prognosis in patients with HF.

Trends in heart failure mortality in Poland between 1980 and 2010.

INTRODUCTION:  Data regarding standardized trends in mortality from heart failure (HF) in the general population are limited. OBJECTIVES:  The aim of the study was to evaluate trends in HF mortality in Poland in the years 1980-2010. PATIENTS AND METHODS:  An analysis of a database of mortality records from 1980-2010 based on National Statistics was performed. Mortality trends for HF by age and sex were analyzed by polynomial or linear regression. RESULTS:  Total crude numbers of HF deaths in 1980 were 21,519 and 23,008 for women and men, respectively, whereas, in 2010, there were 23,304 and 19,558. There was a significant change in mortality trends for HF, from a decline during the first phase of the study to an increase during the most recent years, 2005-2010 (P <0.005 for changes of trends for both sexes). The lowest value reached in 2005 constituted 47% and 41% of the baseline for women and men, respectively. These ratios increased to 59% and 52% in 2010. Stratification by age and sex brought similar results, with the exception of the youngest groups, which showed initial increases in the rates for the years 1980-1985. CONCLUSIONS:  There was a significant decline in the rates of HF mortality in the Polish population for both men and women, showing a maximal reduction of about 50% around 2005. However, between 2005 and 2010, a significant increase in the rates of HF mortality was observed (crude difference equaled 12% for women and 11% for men). It is unknown whether this is a temporary or permanent trend, and the issue requires further investigation.

Myocardial iron homeostasis in advanced chronic heart failure patients.

BACKGROUND: Although, correction of iron deficiency and/or anemia in heart failure (HF) with iron seems promising, little is known about myocardial iron load and homeostasis. Moreover iron supplementation indications are solely based on iron serum markers. The purpose was to assess myocardial iron (M-Iron), ferritin (M-FR), transferrin receptor (M-sTfR) in HF in relation to serum Iron markers. METHODS AND RESULTS: Study group 33 patients, left/right ventricle (LV/RV) (LVEDV 245 ± 84 ml; LVESV 189 ± 85 ml; LVEF 22 ± 11%; RVD 32 ± 10 mm), NTproBNP (5464 ± 4825 pg/ml). Iron homeostasis assessment serum: iron, FR, transferrin/saturation (TSAT), sTfR; myocardial: M-Iron (Instrumental Neutron Activation Analysis, µg/g), M-FR, M-sTfR (ELISA - ng/mg protein) in the explanted failing hearts (FH), compared to non-failing hearts (NFH n=11). In FH as compared to NFH, M-Iron was reduced in RV (174 ± 45 vs 233 ± 97, respectively, p=0.07), LV (189 ± 58 vs 265 ± 119, p=0.04), without significant changes in M-FR/M-sTfR. Out of all serum iron markers only sTfR was negatively correlated with M-Iron in either ventricle (RV r=-0.44, p=0.03, LV r=-0.38, p=0.07). With regard to serum iron status, based on TSAT, patients were divided into two subgroups: reduced (TSAT<15%; n=11) and not-reduced serum iron (TSAT ≥ 15%; n=22). Both subgroups had similar grade of LV/RV dysfunction, NT-proBNP levels. M-FR was lower in TSAT<15% than in TSAT ≥ 15% (LV -31 ± 26 vs 46 ± 29; p=0.07) and (RV -24 ± 24 vs 43 ± 29; p=0.02), without differences in M-Iron and M-sTfR. CONCLUSIONS: In HF, M-Iron levels were reduced. Serum iron markers did not reflect M-Iron levels, except for serum sTfR. In reduced serum iron group, decrease in myocardial storage protein M-FR was observed.

Is evaluation of complex polymorphism helpful in the assessment of prognosis after percutaneous coronary intervention. A prospective study.

BACKGROUND: Coronary artery disease (CAD) is a complex disorder accounting for the majority of cardiovascular deaths and morbidity. It is believed that genetic factors explain part of the excessive risk of major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI). AIM: To evaluate the influence on long-term prognosis of some genetic polymorphisms affecting renin-angiotensin system, inflammatory response, beta-2 adrenergic receptor, nitric oxide and platelets activity in patients with stable CAD undergoing routine PCI. METHODS: The study population consisted of 110 consecutive male patients with stable angina undergoing elective, single-vessel PCI. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism-based techniques. Follow-up data were obtained by postal questionnaires regarding survival, myocardial infarction and revascularisation procedures. The control group consisted of 78 healthy males. RESULTS: Compared to controls, the distribution of polymorphisms among patients differed with regard to interleukin-1 receptor antagonist and CD14 variants. Patients who had PCI during follow-up in comparison with the remaining patients had a similar genetic profile, but higher triglycerides (1.9 vs 1.5 mmol/L, p = 0.01) and atherogenic index (3.8% vs 3.1%, p = 0.03) and lower percentage of HDL (21.8% vs 25.0%, p = 0.02). Among subjects with any revascularisation procedures, a similar clinical profile was observed. However, they differed from those without any procedures regarding the distribution of angiotensinogen M235T variants (MM%/TM%/TT%) 28%/64%/8% vs 19%/50%/31%, p = 0.048. Stratification for myocardial infarction showed association with selectin E variants (AA%/AC%/CC%) 57.1%/28.6%/14.3% vs 78.8%/21.2%/0%, p = 0.055 and higher triglycerides (2.11 vs 1.57 mmol/L, p = 0.055). CONCLUSIONS: Although we cannot exclude the role of polymorphism in angiotensinogen and selectin E genes, the prognosis of patients post-PCI in our study was mainly influenced by risk factors related to lipid metabolisms.

Characteristics of the heart failure population in Poland: ZOPAN, a multicentre national programme.

BACKGROUND: It is difficult to define the optimal management of elderly heart failure (HF) patients with complex comorbidities. Thus, comprehensive characterisation of HF patients constitutes a crucial pre-condition for the successful management of this fragile population. AIM: To analyse the 'real life' HF patients, including the evaluation of their health conditions, management and their use of public health resources. METHODS AND RESULTS: We examined 822 consecutive patients diagnosed with HF in NYHA classes II-IV in primary care practices. The mean age was 68.5 years, and 56% were male. Only 23% of the patients who were of pre-retirement age remained professionally active. Ischaemic or hypertension aetiology was found in 90% of participants. Nearly all patients had multiple comorbidities. Most patients received converting enzyme inhibitors (88%) and beta-blockers (77%), 60% of them both, although dosing was frequently inadequate. During the six months preceding the study, 31% had cardiovascular hospitalisation and 66% required unscheduled surgery visits. CONCLUSIONS: The real life HF population differs from trial populations. Most of the real life patients who had not yet reached retirement age were professionally inactive, mainly due to a disability caused by cardiovascular conditions. Moreover, extremely few participants were free from any comorbidity. Compared to 20th century Polish data, there has been an improvement in the overall quality of HF-recommended pharmacotherapy. It must be stressed, however, that the percentage of those on optimal dosage remains unsatisfactory.

Heart failure patients from hospital settings in Poland: population characteristics and treatment patterns, a multicenter retrospective study.

BACKGROUND: Despite physicians' increasing knowledge regarding heart failure (HF), a significant percentage of patients still do not receive adequate treatment. The aim of this multicentre, retrospective descriptive study was to reveal the pharmacotherapy patterns in HF patients hospitalized in cardiology (CARD) and internal medicine (INT) wards in Poland. METHODS: Included into the study were 800 consecutive patients who were admitted to the hospitals: 350 patients from 7 CARD wards and 450 patients from 9 INT wards. RESULTS: The average age in the study group was about 70 years (youngest participant under 40 and oldest at 95 years of age). Decompensation of HF or acute HF were the most frequent causes of hospitalization (in both groups > 50%). The main etiology was coronary artery disease, either alone or together with hypertension (from about 60% in INT patients to about 78% in CARD patients, p = NS). With regard to pharmacotherapy, angiotensin converting enzyme inhibitors were used in 81% of cases (77% CARD and 83% INT; p = 0.05); out of this group, doses were at optimal or larger in 39.3% of patients (38% CARD patients and 39.4% INT patients). Beta-blockers were administered in 31.4% and 19.1% of patients from the CARD and INT groups respectively (p < 0.0001), but optimal dosing was negligible. CONCLUSIONS: Compared with an assessment conducted several years ago, the past education initiatives have significantly improved the quality of standard-based HF treatment. However, suboptimal dosing and the use of drugs that do not improve prognosis remain an unresolved issue in this population.

A survey of outpatient management of elderly heart failure patients in Poland-treatment patterns.

BACKGROUND: Despite the fact that heart failure constitutes a major health problem there are only limited data regarding pharmacotherapy along with characterization and prognosis of heart failure in the community. AIM: The aim of this study was to investigate treatment pattern in ambulatory patients with heart failure. METHODS: The study is a cross-country epidemiological survey, based on registration, by 417 participating physicians, 50 consecutive ambulatory patients aged >/=65 years seeking medical care for any cause. RESULTS: From a total of 19,877 individuals, 10,579 patients (3901 men and 6678 women, 53% of total) were diagnosed with HF. Therapy with angiotensin converting enzyme inhibitors was recommended in 68%, long acting nitrates in 62%, diuretics in 55%, cardiac glycosides in 31%, Ca blockers in 29% and beta blockers in 22% of all individuals with HF. The prevalence of particular groups of drugs administered in both genders was similar with the exception for calcium blockers, which were more frequently used in women (p<0.001), whereas long acting nitrates in men (p<0.001). In general, angiotensin converting enzyme inhibitors, long acting nitrates and cardiac glycosides use increased with age. On the contrary, beta blockers and calcium blockers were given mostly to younger patients. The most sick patients were more likely to receive angiotensin converting enzyme inhibitors, cardiac glycosides, long acting nitrates and diuretics, whereas less frequently beta blockers and calcium blockers. Combination therapy was used relatively rarely, with lowest percentage in NYHA IV. CONCLUSION: Compared to the other population studies, both angiotensin converting enzyme inhibitors and beta blockers were used relatively more frequently, although in the absolute terms the latter was clearly underused. The high rate of Ca blockers prescription is a matter of concern. More attention should be paid to optimising combination usage and introducing beta blockers early in all stable patients.

Is the decrease of cardiovascular mortality in Poland associated with the reduction of global cardiovascular risk related to changes in life style?

BACKGROUND: After an ascending trend of cardiovascular mortality, which was observed up to the sixties, there was a declining tendency in western countries thereafter. The decrease in mortality rates in Poland has been noticed since 1991. There is an uncertainty whether this improvement in prognosis was only due to the improvement in health care level or was accomplished, to some extent, by population life style changes. AIM: To assess whether the decrease in cardiovascular mortality in Poland was accompanied by a simultaneous reduction in global cardiovascular risk profile. METHODS: The study was based on screened random samples from the Warsaw population aged 35-64 years, who were examined in the years 1984 (2646 subjects), 1988 (1433 subjects), 1993 (1539 subjects) and 2001 (853 subjects). The group evaluated in 1984 was followed up for 10 years with all fatal events recorded (364 deaths were registered including 166 cardiovascular deaths). The model of 10 years probability of total and cardiovascular death was developed, which was based on 11 risk factors (age, smoking cigarettes, systolic blood pressure, pulse pressure, ratio of total cholesterol/HDL-cholesterol, triglyceride, symptoms of coronary heart disease or heart failure, death of mother before 65 or death of father before 55 years due to myocardial infarction or stroke, energy in daily food intake and percentage of energy derived from saturated fatty acids). This model was applied to assess the probability of deaths between years 1984 and 2001, utilising data from screenings. RESULTS: The probability of death (in %) decreased from 1984 to 2001 by 11% in men. However, it remained stable for women. On the other hand the probability of cardiovascular death decreased by 25% and 33%, respectively. The main role in global risk decrease was played by beneficial trends in mean systolic blood pressure (in both genders) and percentage of smokers in men. CONCLUSIONS: Modification of life style influencing risk factors profile decreased the probability of death in the Warsaw population, correlating with changes in mortality rates.

Role of nondiagnostic exercise-induced ST-segment abnormalities in predicting future coronary events in asymptomatic volunteers.

BACKGROUND: Whether exercise-induced ST-segment depression <1 mm is an independent predictor of future coronary events (CEs) in asymptomatic subjects is unknown. METHODS AND RESULTS: We performed maximal treadmill exercise tests on 1083 volunteers from the Baltimore Longitudinal Study of Aging who were free from clinical coronary heart disease. Exercise ST-segment changes were stratified by Minnesota code criteria: 11:1 (n=213), flat or downsloping ST depression > or =1 mm; 11:2 (n=66), flat or downsloping ST depression > or =0.5 mm and <1 mm; 11:4 (n=124), ST-J depression > or =1 mm with slowly rising ST segments; and 11:5 (n=69), minor ST depression (<0.5 mm) before exercise that worsened to flat or downsloping ST depression > or =1 mm during or after exercise. Risk of CE was compared with subjects with normal exercise ECG (n=611). Over a mean follow-up of 7.9 years, 76 subjects developed CEs (angina pectoris, myocardial infarction, or coronary death). On univariate analysis, age (relative risk [RR]=1.07/year, P<0.0001), male sex (RR=1.98, P=0.009), plasma cholesterol (RR=1.02/mg per dL, P<0.0001), hypertension (RR=2.23, P=0.002), duration of exercise (RR=0.71/min, P=0.0001), and systolic blood pressure at peak effort (RR=1.02/mm Hg, P=0.002) were associated with CE. By Cox proportional hazards analysis, age (RR=1.06/year, P<0.0001), male sex (RR=2.76, P=0.0002), plasma cholesterol (RR=1.02 per 1 mg/dL, P<0.0001), duration of exercise (RR=0.87/min, P=0.004), and ST-segment changes coded as either 11:1 (RR=2.70, P=0.0005) or 11:5 (RR=2.73, P=0.04) were independent predictors of CE. CONCLUSIONS: Both a classic ischemic ST-segment exercise response and intensification of minor preexercise ST-segment depression to levels > or =1 mm independently predicted future CE in this asymptomatic population. Neither slowly rising ST depression nor horizontal ST depression <1 mm was prognostic.