Abstract: Receiver operating characteristic (ROC) curves play a central role in the evaluation of biomarkers and tests for disease diagnosis. Predictors for event time outcomes can also be evaluated with ROC curves, but the time lag between marker measurement and event time must be acknowledged. We discuss different definitions of time-dependent ROC curves in the context of real applications. Several approaches have been proposed for estimation. We contrast retrospective versus prospective methods in regards to assumptions and flexibility, including their capacities to incorporate censored data, competing risks and different sampling schemes. Applications to two datasets are presented.
Abstract: Pre- and postsynaptic cardiac sympathetic function is altered in ischemic congestive heart failure (CHF). Whether there is a presynaptic-to-postsynaptic mismatch or whether mismatch is related to adverse cardiac events is unknown. METHODS: In 13 patients with ischemic CHF and 25 aged-matched healthy volunteers, presynaptic function was measured by PET of (11)C-meta-hydroxyephedrine ((11)C-mHED), a norepinephrine (NE) analog. Postsynaptic function, beta-adrenergic receptor (BAR) density (B'(max)), was measured by imaging (11)C-CGP12177. Myocardial blood flow (MBF) was measured by imaging (15)O-water. Each heart was analyzed both globally and regionally, excluding infarcted regions, and a mismatch score, defined as the ratio of B'(max) to NE uptake (PS(nt))(,) was used to indicate mismatch of post- and presynaptic function. RESULTS: Global and regional MBF was not different between CHF and healthy subjects. The global measure of PS(nt) was lower in CHF (0.32 +/- 0.34) than that in healthy subjects (0.81 +/- 0.33, P < 0.0001) and in all 12 regions. Global B'(max) tended to be lower in CHF than that in healthy subjects (10.0 +/- 6.4 pmol/mL vs. 13.4 +/- 4.2, P = 0.056) and in all 12 regions. The global mismatch score (B'(max):PS(nt)) in CHF patients was significantly greater than that in healthy subjects (50.3 +/- 50.7 vs. 19.3 +/- 9.7, P = 0.005) and also greater in 11 of 12 regions. After 1.5 y of follow-up, 4 individuals had an adverse outcome (CHF death, new or recurrent sudden death, or progressive CHF leading to transplantation). Three of the 4 had mismatch scores > 3 times that of the healthy subjects or the CHF patients without an adverse outcome. CONCLUSION: Mismatch between pre- and postsynaptic left ventricular sympathetic function is present in patients with severe CHF and may be more marked in those with adverse outcomes.
Abstract: BACKGROUND: Pro-inflammatory cytokines may contribute to the development and progression of heart failure (HF) and are also implicated in depressive disorders. In this cross-sectional study, we investigated whether systemic inflammation, as assessed by circulating levels of inflammatory cytokines, was associated with comorbid depression in patients with heart failure. METHODS AND RESULTS: Baseline clinical variables, depression status, and inflammatory marker levels were measured in 129 ambulatory HF patients. We hypothesized that pro-inflammatory cytokines, specifically tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6, would be elevated in HF patients with comorbid depression. In unadjusted analyses, levels of soluble TNF-alpha receptor1 (sTNFr1) were significantly higher among depressed (1.6 ng/mL), compared with nondepressed (1.1 ng/mL), HF patients (P = .01). After multivariate adjustment, compared with patients in the lowest quartile of sTNFr1 levels, those in the highest quartile had an adjusted near 5-fold higher risk of depression (OR 4.6, 95% CI 1.2-17.3; P for trend .008). The subgroup of patients on antidepressants but not currently depressed had a trend toward higher levels of sTNFr1, suggesting that antidepressants may not lower cytokine levels even when adequately treating depressive symptoms. IL-1beta and IL-6 levels were not significantly different among depressed versus nondepressed HF patients. CONCLUSIONS: In this cross-sectional analysis, HF patients with comorbid depression, compared with nondepressed HF patients, had higher levels of sTNFr1 and trend toward higher levels of sTNFr1 even when adequately treated for depression.
Abstract: BACKGROUND: Patient-centered health status measures are important because they capture the patient's perspective on their heart failure, but it is unclear which of these have independent prognostic significance. METHODS AND RESULTS: A total of 142 consecutive subjects from a specialty heart failure clinic were assessed at baseline with a broad array of clinical, laboratory, and self-report measures including four summary measures of health status. The relationships between these measures and their association with the combined end point of transplantation or death over a mean follow-up of 3 years were examined. In unadjusted analyses, the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score had the strongest association with the combined end point (HR [for each unit score difference] = 0.98 [0.96-0.99], P = .002). In the adjusted Cox proportional hazards model including all 4 summary measures, the Seattle Heart Failure Score, V0(2,) systolic blood pressure, and medical comorbidity, only the Standard Gamble utility remained significantly associated with time to the combined end point (HR [for each 0.01 utility score difference] = 0.98 [0.97-0.99], P = .007). CONCLUSIONS: Our study suggests that summary health status measures are simple and significant indicators of prognosis in advanced heart failure patients. The KCCQ summary score summarizes a wide range of clinical variables from the patient's point of view, whereas the standard gamble utility contains important prognostic information not captured in usual clinical variables.
Abstract: INTRODUCTION: Patients with chronic heart failure (CHF) have a lower peak oxygen consumption (pVO2) than normal subjects, and for a given quantity of work, have a lower total oxygen consumption (VO2) than controls. This apparent increase in biomechanical efficiency (BE) might be due to a higher proportion of anaerobic metabolism which, although leading to lower VO2 during steady state exercise, must be compensated for during recovery. METHODS: 13 patients with stable CHF and 12 controls underwent peak cycle exercise testing followed by three separate steady state exercise tests at 15%, 25% and 50% of the peak workload in random order. Oxygen consumption at steady state, deficit (during onset) and debt (during recovery) were calculated. BE was estimated as the total oxygen required to perform a given quantity of work. RESULTS: Patients had lower pVO2 and peak workload than control subjects. Absolute oxygen deficit and debt as a percentage of total oxygen consumed during the steady state tests was the same in both groups. However, once controlled for workload, VO2 deficit, debt and uptake at steady state were greater in patients than controls for the tests at 15% and 25% of peak. BE was inversely related to peak oxygen consumption in controls and patients. CONCLUSIONS: Patients with CHF have impaired BE at low work loads when compared with normal subjects.
Abstract: BACKGROUND: Prognosis and mode of death in heart failure patients are highly variable in that some patients die suddenly (often from ventricular arrhythmia) and others die of progressive failure of cardiac function (pump failure). Prediction of mode of death may facilitate decisions about specific medications or devices. METHODS AND RESULTS: We used the Seattle Heart Failure Model (SHFM), a validated prediction model for total mortality in heart failure, to assess the mode of death in 10,538 ambulatory patients with New York Heart Association class II to IV heart failure and predominantly systolic dysfunction enrolled in 6 randomized trials or registries. During 16,735 person-years of follow-up, 2014 deaths occurred, which included 1014 sudden deaths and 684 pump-failure deaths. Compared with a SHFM score of 0, patients with a score of 1 had a 50% higher risk of sudden death, patients with a score of 2 had a nearly 3-fold higher risk, and patients with a score of 3 or 4 had a nearly 7-fold higher risk (P<0.001 for all comparisons; 1-year area under the receiver operating curve, 0.68). Stratification of risk of pump-failure death was even more pronounced, with a 4-fold higher risk with a score of 1, a 15-fold higher risk with a score of 2, a 38-fold higher risk with a score of 3, and an 88-fold higher risk with a score of 4 (P<0.001 for all comparisons; 1-year area under the receiver operating curve, 0.85). The proportion of deaths caused by sudden death versus pump-failure death decreased from a ratio of 7:1 with a SHFM score of 0 to a ratio of 1:2 with a SHFM score of 4 (P trend <0.001). CONCLUSIONS: The SHFM score provides information about the likely mode of death among ambulatory heart failure patients. Investigation is warranted to determine whether such information might predict responses to or cost-effectiveness of specific medications or devices in heart failure patients.
Abstract: Management of heart failure (HF) remains complex with low 5-year survival. The Seattle Heart Failure Model (SHFM) is a recently described risk score derived predominantly from clinical trial populations that may enable the prediction of survival in patients with HF. This study sought to validate the SHFM in an independent, nonclinical trial-based HF population. Patients (n = 4,077) from the hospital-based Intermountain Heart Collaborative Study registry with a diagnosis of HF were evaluated using prospectively collected data (mean +/- SD follow-up 4.4 +/- 3.1 years). The SHFM was used to calculate a risk score for each patient. Receiver-operating characteristic area under the curve provided SHFM predictive ability for a composite end point of survival free from death, transplantation, or left ventricular assist device implantation. Addition of creatinine, serum urea nitrogen, diabetes status, and B-type natriuretic peptide (BNP) to the SHFM was also evaluated. Patient age averaged 67 +/- 13 years and 61% were men. Area under the curves were 0.70 (95% confidence interval 0.66 to 0.70), 0.67 (95% confidence interval 0.66 to 0.69), 0.67 (95% confidence interval 0.065 to 0.68), and 0.66 (95% confidence interval 0.63 to 0.67) for 1-, 2-, 3-, and 5-year survivals, respectively. Area under the curves were slightly attenuated in patients >75 years of age (n = 1,339), implantable cardioverter-defibrillator recipients (n = 693), and patients with an ejection fraction >40% (n = 1,634). BNP added significantly to the model (area under the curve +0.06). BNP was found to add additional predictive ability at 1 year (area under the curve change +0.05) and nominally at 5 years (area under the curve change +0.02). In conclusion, the SHFM predicts survival in patients with HF in a hospital-based population, with areas under the curve similar to those from data on which models were initially fit.
Abstract: BACKGROUND: Patients with advanced heart failure (HF) have an uncertain prognosis and low rates of advance care planning and hospice use. The purpose of this study was to describe how patients view and plan for their future. METHODS: Twenty-four (N = 24) patients took part in a semistructured interview in which they were asked to describe their experiences in living with heart disease and their understanding and planning for their future. Interviews were transcribed and analyzed using the constant comparative method to generate a grounded theory. RESULTS: The core category, "Living with HF," encompassed the subcategories of "My Experience of HF," "Help with HF," and "My Future with HF." This article reports on "My Future with HF." Patients wanted to discuss how HF affected their future with their providers, but initiation of these discussions was difficult and the absence of discussion led to frustration. Patients did not find specific life expectancy estimates helpful in coping or planning their future care. CONCLUSIONS: Patients with advanced HF do not plan well for end-of-life care and tend to drift along while vaguely hoping for the best. End-of-life care in advanced HF should address difficulties in decision making and provider communication.
Abstract: INTRODUCTION: Prior investigations in post-myocardial infarction and healthy elderly subjects have established that heart rate variability (HRV) predicts mortality. Predominantly cross-sectional studies have shown an association between endurance training and measures of HRV. In a randomized trial, this study sought to prospectively compare the effects of endurance and strength training on HRV in 45 healthy elderly females (average age 69.9 +/- 0.9 years). METHODS: All subjects were rigorously screened to be normal by history, physical, blood tests, ECG, ETT and echocardiogram. All subjects were monitored for 24 hours by a 2-channel Holter before and after training. Artifacts and arrhythmias were manually removed. Tapes were examined for standard measures of HRV. INTERVENTION: 15 subjects were randomized to endurance trained (ET), 15 subjects to strength training (ST), and 15 subjects to no training (NT) for six months. RESULTS: Training resulted in a significant increase in VO2max in the ET (+7.4%, p = 0.005) group only. There was a small but not significant decrease in HR with both the ET and ST groups. ET resulted in a significant increase in most time domain and all frequency domain measures of HRV. ST resulted in no significant change in HRV measures. CONCLUSION: Strength training, as opposed to endurance training has no significant impact on HRV. This suggests that exercise interventions designed to improve strength (such as weight-lifting) will have little to no impact on HRV, suggesting that aerobic and strength training operate through different mechanisms to reduce cardiac risk.
Abstract: OBJECTIVES: To determine if centrally reducing sympathetic tone with clonidine will reverse the downregulation in the alpha-adrenergic (alphaAR) and beta-adrenergic (betaAR) responses seen with normal aging. METHODS: Twelve rigorously screened young adult (mean age, 26 years) and 15 older adult (mean age, 69 years) subjects were studied before and after using the clonidine patch (TTS-2) for 2 weeks. betaAR (isoproterenol at 35 ng/kg/min) and alphaAR (phenylephrine at 1.0 microg/kg/min) were assessed using radionuclide measures of end diastolic, end systolic, and stroke volume indices, cardiac index, and ejection fraction. RESULTS: Clonidine reduced resting plasma norepinephrine and this reduction was greater in older subjects (-47 +/- 3 versus -26 +/- 6%, P = 0.001). After 2 weeks of clonidine patch, upregulation of the betaAR was significantly higher in young subjects for heart rate (+10.7 +/- 1.5 versus +4.6 +/- 1.5 bpm; P = 0.01). There was no significant age-associated difference in the upregulation of the alphaAR with clonidine for systolic, diastolic, and mean blood pressure or systemic vascular resistance. CONCLUSIONS: With aging, there is an impaired resensitization of the chronotropic betaAR response with central sympathetic downregulation that is not seen with the alphaAR.
Abstract: We report a case of Chagas' cardiomyopathy confirmed in a patient after heart transplantation. The patient initially presented with symptoms of congestive heart failure and was found to have positive serology for prior Trypanosoma cruzi infection. Despite optimal medical management, the patient had deterioration of his cardiac function and he underwent heart transplantation. Pathology examination of the explanted heart confirmed Chagas' cardiomyopathy. The cardiac sequelae of Chagas' disease include arrhythmias, aneurysm, thromboembolism, cardiomyopathy, and sudden death. We review the epidemiology, cardiac pathology, and evaluation of patients with Chagas' cardiac disease. We discuss the clinical features of Chagas' cardiomyopathy and available treatments including cardiac transplantation.
Abstract: BACKGROUND: Heart failure has an annual mortality rate ranging from 5% to 75%. The purpose of the study was to develop and validate a multivariate risk model to predict 1-, 2-, and 3-year survival in heart failure patients with the use of easily obtainable characteristics relating to clinical status, therapy (pharmacological as well as devices), and laboratory parameters. METHODS AND RESULTS: The Seattle Heart Failure Model was derived in a cohort of 1125 heart failure patients with the use of a multivariate Cox model. For medications and devices not available in the derivation database, hazard ratios were estimated from published literature. The model was prospectively validated in 5 additional cohorts totaling 9942 heart failure patients and 17,307 person-years of follow-up. The accuracy of the model was excellent, with predicted versus actual 1-year survival rates of 73.4% versus 74.3% in the derivation cohort and 90.5% versus 88.5%, 86.5% versus 86.5%, 83.8% versus 83.3%, 90.9% versus 91.0%, and 89.6% versus 86.7% in the 5 validation cohorts. For the lowest score, the 2-year survival was 92.8% compared with 88.7%, 77.8%, 58.1%, 29.5%, and 10.8% for scores of 0, 1, 2, 3, and 4, respectively. The overall receiver operating characteristic area under the curve was 0.729 (95% CI, 0.714 to 0.744). The model also allowed estimation of the benefit of adding medications or devices to an individual patient's therapeutic regimen. CONCLUSIONS: The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival with the use of easily obtained clinical, pharmacological, device, and laboratory characteristics.
Abstract: OBJECTIVES: This study sought to assess the potential utility of impedance cardiography (ICG) in predicting clinical deterioration in ambulatory patients with heart failure (HF). BACKGROUND: Impedance cardiography uses changes in thoracic electrical impedance to estimate hemodynamic variables, but its ability to predict clinical events has not been evaluated. METHODS: We prospectively evaluated 212 stable patients with HF and a recent episode of clinical decompensation who underwent serial clinical evaluation and blinded ICG testing every 2 weeks for 26 weeks and were followed up for the occurrence of death or worsening HF requiring hospitalization or emergent care. RESULTS: During the study, 59 patients experienced 104 episodes of decompensated HF (16 deaths, 78 hospitalizations, and 10 emergency visits). Multivariate analysis identified 6 clinical and ICG variables that independently predicted an event within 14 days of assessment. These included three clinical variables (visual analog score, New York Heart Association functional class, and systolic blood pressure) and three ICG parameters (velocity index, thoracic fluid content index, and left ventricular ejection time). The three ICG parameters combined into a composite score was a powerful predictor of an event during the next 14 days (p = 0.0002). Visits with a high-risk composite score had 2.5 times greater likelihood and those with a low-risk score had a 70% lower likelihood of a near-term event compared with visits at intermediate risk. CONCLUSIONS: These results suggest that when performed at regular intervals in stable patients with HF with a recent episode of clinical decompensation, ICG can identify patients at increased near-term risk of recurrent decompensation.
Abstract: OBJECTIVES: The aim of this study was to determine whether changes in oxygen efficiency occur with aging or exercise training in healthy young and older subjects. BACKGROUND: Exercise capacity declines with age and improves with exercise training. Whether changes in oxygen efficiency, defined as the oxygen cost per unit work, contributes to the effects of aging or training has not yet been defined. METHODS: Sixty-one healthy subjects were recruited into four groups of younger women (ages 20 to 33 years, n = 15), younger men (ages 20 to 30 years, n = 12), older women (ages 65 to 79 years, n = 16), and older men (ages 65 to 77 years, n = 18). All subjects underwent cardiopulmonary exercise testing to analyze aerobic parameters before and after three to six months of supervised aerobic exercise training. RESULTS: Before training, younger subjects had a much higher exercise capacity, as shown by a 42% higher peak oxygen consumption (VO2) (ml/kg/min, p < 0.0001). This was associated with an 11% lower work VO2/W (p = 0.02) and an 8% higher efficiency than older subjects (p = 0.03). With training, older subjects displayed a larger increase in peak W/kg (+29% vs. +12%, p = 0.001), a larger decrease in work VO2/W (-24% vs. -2%, p < 0.0001), and a greater improvement in exercise efficiency (+30% vs. 2%, p < 0.0001) compared to the young. CONCLUSIONS: Older age is associated with a decreased exercise efficiency and an increase in the oxygen cost of exercise, which contribute to a decreased exercise capacity. These age-related changes are reversed with exercise training, which improves efficiency to a greater degree in the elderly than in the young.
Abstract: In observational studies, statins are associated with lower mortality in patients with heart failure (HF), including those with nonischemic HF. Such benefits could be related to anti-inflammatory effects; however, the effects of statins on systemic inflammation in HF are not well-established. We conducted a 16-week, single-center, randomized, double-blind, placebo-controlled, crossover clinical trial of the effects of atorvastatin 10 mg/day on concentrations of systemic inflammatory markers in 22 patients with HF (including 20 with nonischemic HF) with New York Heart Association class II or III symptoms and left ventricular ejection fraction of <40%. The absolute and percentage of changes in inflammatory marker levels were evaluated using analysis of variance. Statin treatment reduced the concentrations of soluble tumor necrosis factor receptor-1 by 132 pg/ml (p = 0.04) and 8% (p = 0.056), C-reactive protein by 1.6 mg/L (p = 0.006) and 37% (p = 0.0002), and, after adjustment for treatment order, endothelin-1 by 0.21 pg/ml (p = 0.007) and 17% (p = 0.01). In post hoc analyses, the reduction in tumor necrosis factor receptor-1 levels was highest among patients with elevated levels at baseline (at or higher than the median of 1,055 pg/ml, p interaction = 0.001), among whom statin therapy reduced the levels by 306 pg/ml (p <0.001) and 22% (p <0.001). Statin treatment did not significantly affect the levels of other inflammatory markers, including interleukin-6 and brain natriuretic peptide. In conclusion, short-term atorvastatin therapy reduced the levels of several important inflammatory markers in patients with HF.
Abstract: The usefulness of low relative lymphocyte count as an independent predictor of death/urgent transplant in patients with heart failure (HF) and the association between low relative lymphocyte count and neurohormone and cytokine activation were investigated. Relative lymphocyte count, clinical variables, neurohormones, and cytokines were measured in 129 outpatients with HF. Follow-up extended to a mean of 3.0 +/- 1.2 years for death/urgent transplant. Low relative lymphocyte count was independently associated with a 3.4-fold increased risk of death/urgent transplant. Relative lymphocyte count was positively associated with hemoglobin and inversely associated with age, jugular venous pressure, creatinine, leukocyte count, and soluble tumor necrosis factor receptor-1. There was only a borderline inverse association with cortisol levels during evening hours.
Abstract: BACKGROUND: Depression impairs health status among patients with coronary disease. The effect of depression on patients with heart failure has been studied to date only in hospitalized patients. METHODS AND RESULTS: Prospective cohort study of 113 outpatients with advanced heart failure. At baseline, 19% (n = 21) had major depression or dysthymia, 9% (n = 10) had minor depression, and 72% (n = 82) had no current depression diagnosis. Repeated measures analyses of covariance adjusting for demographic and clinical differences demonstrated that the depression groups differed on observed function (6-minute walk distance [F = 4.8, P = .01]), and self-reported generic (SF-36) and disease-specific (Kansas City Cardiomyopathy Questionnaire) health status. Depression groups also differed in severity of self-reported breathlessness, chest pain, and fatigue. Subject- and spouse-reported role function also differed between the groups. Partial correlation (controlling for the same covariates) between baseline Hamilton Depression Scale scores and these outcomes was highly significant at baseline and follow-up. CONCLUSIONS: Depression is prospectively associated with poorer health status in patients with advanced heart failure. Physical and role function, symptom severity, and quality of life are all significantly affected.
Abstract: Experimental considerations suggest both potential harm and benefit from statin therapy in patients with severe heart failure. However, relations of statin therapy with clinical outcomes in severe heart failure are not well established. Using data from the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we evaluated associations of statin therapy with total mortality among 1,153 patients with severe heart failure (ejection fraction <30% and New York Heart Association class IIIB or IV symptoms) of ischemic and nonischemic etiologies. Statin therapy was administered to 134 patients (12%) during the study period. Over a 1.3-year mean follow-up, there were 413 deaths (29 deaths/100 person-years). Adjusting for age, gender, diabetes, smoking, heart failure etiology, ejection fraction, and New York Heart Association class, statin therapy was associated with a 62% lower risk of death (hazard ratio 0.38, 95% confidence interval 0.23 to 0.65), or 1 fewer death/5 patients taking statin therapy for 1 year. This association was not greatly altered by additional adjustment for a variety of other patient characteristics, including serum cholesterol levels. After propensity score analyses, statin therapy was still associated with a 48% lower risk of death (hazard ratio 0.52, 95% confidence interval 0.30 to 0.89). Although this observational study does not prove causality, further investigation of potential benefits of statins in patients with severe heart failure appears warranted.
Abstract: BACKGROUND: Previous studies of biomechanical efficiency (external work/energy input--Watt/O(2) consumed) in heart failure (HF) using cardiopulmonary exercise testing (CPET) and magnetic resonance spectroscopy (MRS) have had discordant results with increased efficiency by CPET and decreased efficiency by MRS. AIMS: Compare biomechanical efficiency of HF subjects and normal controls during steady state (SS=35 W for 6 min) and ramp cycle ergometer exercise. The hypothesis was that HF subjects would have impaired biomechanical efficiency that correlated with HF symptoms. METHODS: Biomechanical efficiency used the actual Vo(2) during exercise and recovery. Gross (Vo(2) above zero), Net (Vo(2) above the resting Vo(2)) and Work (Vo(2) above the unloaded pedaling Vo(2)) efficiencies were calculated. RESULTS: HF subjects had an 18% higher Vo(2) during SS exercise (P=0.029). Biomechanical efficiency was reduced during SS exercise (gross -15%, P=0.019, net -15%, P=0.062, and work -35%, P=0.002). Gross Efficiency during SS exercise had the strongest correlation with HF symptoms (r=0.55). During ramp exercise gross (-26%), net (-10%) and work (-8%) biomechanical efficiency were all reduced (all P<0.05). The slope of the Vo(2)/Watt relationship during ramp exercise had the best correlation with HF symptoms (r=0.46). CONCLUSIONS: HF subjects have an increased O(2) cost/Watt during SS and ramp exercise that correlates with HF symptoms of fatigue and breathlessness. Methods to improve biomechanical efficiency in HF subjects by exercise training or medications may improve the symptoms and the impaired exercise capacity associated with HF.
Abstract: BACKGROUND: trans fatty acid (TFA) intake increases systemic inflammation in healthy persons. However, the effect in patients with established heart disease is unknown. OBJECTIVE: Our aim was to determine whether TFAs are associated with systemic inflammation in patients with established heart disease. DESIGN: Red blood cell membrane TFAs, a biomarker of dietary intake, and inflammatory marker concentrations were ascertained in 86 ambulatory patients with established heart failure. Associations between TFA levels and inflammatory markers were evaluated by linear regression. RESULTS: Mean (+/-SD) TFA levels were 1.8 +/- 0.4% of membrane fatty acids (range: 0.7-2.9%). For each inflammatory marker, associations are presented as the absolute difference and percentage difference from the mean for each 1% higher membrane TFA level. After adjustment for age, sex, body mass index, diabetes, smoking, ejection fraction, New York Heart Association class, ischemic etiology, statin use, and serum glucose, TFA levels were positively associated with interleukin (IL) 1beta (difference from mean: 0.38 pg/mL; percentage difference from mean: 66%; P=0.04), IL-1 receptor antagonist (4033 pg/mL; 297%; P=0.006), IL-6 (9.5 pg/mL; 123%; P=0.006), IL-10 (241 pg/mL; 183%; P=0.02), tumor necrosis factor (TNF) alpha (256 pg/mL; 249%; P=0.02), TNF receptor 1 (537 pg/mL; 41%; P=0.03), TNF receptor 2 (39 242 pg/mL; 247%; P=0.001), monocyte chemoattractant protein 1 (117 pg/mL; 119%; P=0.004), and brain natriuretic peptide (40 pg/mL; 57%; P=0.04). Further adjustments for other patient characteristics did not significantly alter the results. CONCLUSION: TFAs are strongly associated with systemic inflammation in patients with heart disease, which suggests that attention to TFA intake may be important for secondary prevention efforts.
Abstract: In a prospective cohort study of 142 outpatients with advanced heart failure followed for a mean of 3 years, 29% of subjects with a depression diagnosis at baseline were significantly more likely to experience the combined end point of death or transplantation (hazard ratio 2.54, 95% confidence interval 1.16 to 5.55). After adjustment for a range of sociodemographic and clinical characteristics, patients with depressive disorders were still significantly more likely to reach the combined end point (hazard ratio 2.41, 95% confidence interval 1.24 to 4.68). Depressed patients also had more heart failure related hospitalizations (1.5 +/- 1.8 vs 0.6 +/- 1.4, p = 0.04) and clinic visits (2.4 +/- 1.7 vs 1.7 +/- 1.8, p = 0.04) over the first year of follow-up.
Abstract: P-selectin is a marker of platelet activation. Previous studies have reported elevated P-selectin in patients with congestive heart failure (CHF) and depression as separate disorders. We examined if comorbid depression had an effect on platelet activation in CHF patients. Soluble (s)P-selectin was measured in 108 CHF patients; 24 with comorbid depression. There were no significant differences in age, cardiac parameters or (s)P-selectin levels between CHF-only patients and patients with comorbid depression. Our data show no group differences in P-selectin values, which suggests that comorbid depression has no additive effect on platelet activation in CHF patient.
Abstract: Congestive heart failure is a disorder that includes a multitude of neurohormonal responses that become maladaptive over time. Chronic sympathetic stimulation adversely affects the well-being and survival of heart failure patients and contributes to the exercise intolerance frequently seen in these patients. Norepinephrine levels have been correlated with poorer survival in heart failure patients. Administration of norepinephrine has been shown to impair exercise responses in those with congestive heart failure, and the recent effort to incorporate beta blocker therapy into the standard management of heart failure patients addresses this abnormal neurohormonal process. Studies with central-acting sympatholytics have shown mixed results. The use of drugs such as clonidine has been suggested as potentially useful therapy in the long-term management of patients with heart failure, but definitive conclusions await further study. Regular exercise has been shown to reduce resting norepinephrine levels in heart failure subjects. This may serve as an additional rationale to recommend chronic exercise for these patients.
Abstract: Positron Emission Tomography was used to measure global and regional cardiac beta-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [(11)C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [(11)C]-CGP12177 was used to measure cell surface beta-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.
Abstract: OBJECTIVE: There is a convincing body of evidence linking depression, cardiovascular disease, and mortality. There is also growing evidence that depression is a risk factor for congestive heart failure (CHF) and that CHF patients with major depression have higher rates of mortality and repeat hospitalizations. Currently there are no proposed neurobiological or neuroimmune mechanisms for the comorbidity of heart failure and depression. METHODS: This review focuses on the recent literature about the role of cytokines in CHF and depression as separate conditions. This review also attempts to identify the overlapping immunological mechanisms that have a potential for future research in the pathophysiology of comorbid depression and CHF. RESULTS: Results of current studies suggest that cytokines exert deleterious effects on the heart and that soluble tumor necrosis factor (TNF) receptor 2 leads to reversal of the cardiotoxic effects of TNF, although the clinical significance of this is unclear. Major depression has been associated with alteration of various aspects of the innate immune system, including cellular components (such as microphages, neutrophils, and natural killer cells) and soluble mediators (such as acute-phase reaction proteins and cytokines). It is inconclusive whether antidepressants have immunoregulatory effects. CONCLUSIONS: The literature has not yet addressed the role of cytokines in comorbid depression and CHF. But cytokines may provide a new avenue in understanding brain-body interaction in depression and heart failure.
Abstract: STUDY OBJECTIVES: The oxygen cost during exercise has been reported to be decreased in patients with congestive heart failure (CHF), implying an increased efficiency (lower oxygen uptake [VO(2)] per Watt [VO(2)/W]); however, these studies ignored the oxygen debt that is increased in heart failure. SUBJECTS: The primary aim of this research was to evaluate the total oxygen cost (work VO(2)/W) during exercise and recovery in patients with heart failure as compared with healthy adults. DESIGN AND PATIENTS: We performed a retrospective analysis comparing the exercise VO(2)/W, the recovery VO(2)/W, the work VO(2)/W, and the VO(2)/W relationship above and below the ventilatory threshold (VT) in 11 healthy control subjects and 45 patients with CHF. RESULTS: The exercise VO(2)/W was decreased by 29% (p < 0.0001) in patients with CHF; however, the recovery VO(2)/W was increased by 167% (p < 0.0001) and the work VO(2)/W was increased by 14% in patients with CHF (p = 0.014). The VO(2)/W slope increased above the VT (+ 27%, p = 0.0017) in both normal subjects and patients with CHF, suggesting a decrease in efficiency above the VT. There was an inverse correlation (r = 0.646, p < 0.0001) between exercise VO(2)/W and recovery VO(2)/W, implying that subjects with a low exercise VO(2)/W were not efficient but rather accumulated a large oxygen debt that was repaid following completion of exercise. CONCLUSIONS: Heart failure is associated with lower exercise VO(2)/W; however, the patient with heart failure is not efficient, but rather accumulating a large oxygen debt (recovery VO(2)/W) that is repaid following exercise. In addition, the work VO(2)/W (including both exercise and recovery) is increased in patients with heart failure in comparison to control subjects, and correlates inversely with the percentage of predicted VO(2). The large recovery VO(2)/W is likely due to impaired oxygen delivery to exercising muscle during exercise. The increase in the work VO(2)/W is probably due to changes in skeletal muscle fiber type that occur in patients with heart failure (type I to type IIb).
Abstract: OBJECTIVES: The study was done to determine whether the effects of parasympathetic withdrawal on heart rate, blood pressure (BP), and systolic and diastolic function are altered with normal aging. BACKGROUND: Cardiac responses to beta-adrenergic sympathetic stimulation decline with aging as does the heart rate response to parasympathetic withdrawal, but the extent to which other responses to parasympathetic withdrawal decrease is less clear. METHODS: Heart rate, BP, systolic function, and diastolic filling responses to parasympathetic withdrawal induced by atropine (0.02 mg/kg) were compared in 50 healthy subjects, 28 older (ages 65 to 80 years, mean 70 years; 18 females all on estrogen) and 22 young (age 18 to 32 years, mean 26 years; 12 females) subjects, using radionuclide angiography. RESULTS: Parasympathetic withdrawal in the older group caused less of an increase in heart rate (+33 vs. +48 beats/min), cardiac index (+0.6 vs. +1.5 l/m(2)), systolic blood pressure (-1 vs. +7 mm Hg), and early diastolic filling rate (+1.7 vs. +2.4 end-diastolic volumes/s) (all p < or = 0.01). At similar declines in the diastolic filling period, end-diastolic volume index (EDVI) fell substantially more in the older group (-11.6 vs. -2.4 ml/m(2), p < 0.001). The only gender difference was in diastolic filling rate, which was similar in the young males and females, but significantly less in older males than in older females. CONCLUSIONS: The responses to parasympathetic withdrawal as well as sympathetic stimulation decline with aging, and both contribute to the reduced cardiovascular responses to stress with advancing age.
Abstract: OBJECTIVES: Our aim was to examine the relationships between serum hematocrit (Hct) and risk of all-cause mortality among patients with severe heart failure (HF). BACKGROUND: Anemia occurs with increased frequency in severe HF. However, few studies have examined the impact of anemia on mortality in this population. METHODS: Using a prospective cohort design, we evaluated the relationships between baseline serum Hct and mortality among 1,130 patients with left ventricular EF <30% and New York Heart Association functional class IIIB or IV HF treated with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Mortality was ascertained by centralized adjudication. RESULTS: The mean Hct was 41.8% (range 25.4% to 58.8%). Over 15 months of mean follow-up, there were 407 deaths (29 per 100 person-years). After adjustment for potential confounders, those in the lowest quintile of Hct (range 25.4% to 37.5%) had a 52% higher risk of death (hazard ratio 1.52, 95% confidence interval 1.11 to 2.10), compared with the highest quintile (range 46.1% to 58.8%). Within the lowest quintile of Hct, each 1% decrease in Hct was associated with an 11% higher risk of death (p < 0.01), whereas within the four higher quintiles of Hct, Hct was not associated with total mortality. Evaluation of different causes of death indicated that a lower Hct was strongly associated with death from progressive HF, rather than sudden death or other deaths. CONCLUSIONS: Among patients with severe HF, anemia is a significant independent risk factor for death, with a progressively higher risk with increasing severity of anemia. Further investigation of the etiologies, prevention, and treatment of anemia in severe HF is warranted.
Abstract: BACKGROUND: The occurrence of coronary artery disease (CAD) after heart transplantation may represent an accelerated inflammatory and thrombotic response to coronary vascular endothelial cell injury. Several common mutations involving hemostasis and cellular adhesion proteins have been associated with genetic susceptibility to native coronary heart disease. The clinical setting of heart transplantation provides a unique opportunity to examine the relative contribution of circulating (i.e., recipient) vs local vascular (i.e., donor) hemostatic components to the occurrence of CAD. METHODS: We performed genotyping for several common hemostatic polymorphisms among 53 cardiac transplant patients and their heart donors. Patients were observed for an average of 43 months, and the presence of transplant CAD was determined by coronary angiography. RESULTS: The development of transplant CAD did not relate to recipient hemostatic genotype, but 2 donor polymorphisms (PAI-1 4G/5G and alpha(2) integrin C807T) were important predictors of transplant CAD. The risk ratio (RR) of transplant CAD associated with donor PAI-1 4G/4G genotype was 2.6 (95% confidence interval [CI] 1.1-6.2) and was modified by recipient cytomegalovirus status, hyperlipidemia, diabetes, and recipient factor XIII Val34Leu genotype. The RR of transplant CAD associated with donor alpha(2) integrin 807 T/T genotype was 7.4 (95% CI, 2.5-22.0). CONCLUSIONS: Genetic and metabolic factors contributed by both donor and recipient may interact at the level of the coronary vessel wall in the development of transplant-associated CAD, and this finding may provide additional support for the importance of local thrombotic response to endothelial injury in the pathogenesis of this disorder.
Abstract: A patent infarct-related artery (IRA) following myocardial infarction has been associated with lower mortality, increased systolic function, decreased left ventricular remodeling, and electrical stability. The purpose of this study was to determine whether coronary artery patency early after myocardial infarction is associated with greater early diastolic filling than a closed artery. Radionuclide ventriculograms were performed at a central laboratory on 167 patients who received alteplase for an acute myocardial infarction and had infarct artery patency determined by cardiac catheterization. The peak early filling rate (PEFR) was assessed by 4 different methods: (1) PEFR (EDV/s)--normalized to the end-diastolic volume; (2) PEFR (SV/s)--normalized to the stroke volume; (3) PEFR (ml/s/m(2))--an absolute diastolic filling rate; and (4) PEFR (PER)--normalized to the peak ejection rate. Patients with a closed IRA (n = 16, Thrombolysis In Myocardial Infarction [TIMI] 0 or 1 flow) and patients with an open IRA (n = 151, TIMI 2 or 3 flow) had similar ages, ejection fractions, and cardiac volumes. However, among patients with an occluded IRA, the PEFR was decreased by 12% to 18% by the 4 measures of diastolic filling (3 of 4 methods, p <0.05). PEFR (EDV/s) was 1.69 +/- 0.9 in the occluded group versus 2.06 +/- 0.4 EDV/s in the open artery group (p = 0.005). By multivariate analysis, IRA patency was an independent predictor of the PEFR by all 4 methods. Early coronary artery patency after an acute myocardial infarction preserves diastolic filling. Improved diastolic function may in part explain part of the long-term benefits of a patent IRA after thrombolytic therapy when there is no documented improvement in the ejection fraction.
Abstract: PURPOSE: The primary aim of this research was to evaluate the effect of acute norepinephrine (NE) infusion on the exercise oxygen utilization in heart failure patients as compared with healthy adults. METHODS: Eleven healthy adults and 10 patients with NYHA class II-III heart failure (ejection fraction <40%) who were not on beta-blocker therapy underwent steady state exercise under placebo or NE infusion conditions, followed by maximal ramp exercise testing. Oxygen utilization, hemodynamic responses, and serum lactate NE levels were evaluated. RESULTS: The hemodynamic effects of NE were evident in both groups with statistically significant increases in blood pressure and concomitant decreases in heart rates. Lactate levels were higher in heart failure subjects under all conditions and steady state exercise increased levels by 24% (P = 0.04). NE infusion increased lactate levels by a nonsignificant 24% (P = 0.19). NE infusion tended to increase oxygen consumption (VO2) at the end of steady state exercise in CHF subjects (4% change; P = 0.06). Compared with healthy adults, NE infusion significantly impaired (increased) the gross VO2/W relationship in heart failure subjects (P = 0.037). There was also a modest trend for a worsening (decrease) in net efficiency after NE infusion in CHF subjects. There were no significant adverse effects of low-dose NE infusion in either group. CONCLUSIONS: We conclude that 1) acute low-dose NE infusion impairs the oxygen utilization in stable heart failure patients but not in healthy adults. This may help to explain the exercise intolerance that accompanies congestive heart failure. 2) Acute infusion of low-dose NE infusion is safe and well tolerated in both healthy adults and compensated heart failure patients.
Abstract: Heart rate variability (HRV) (SD of the RR interval), an index of parasympathetic tone, was measured at rest and during exercise in 13 healthy older men (age 60 to 82 years) and 11 healthy young men (age 24 to 32 years) before and after 6 months of aerobic exercise training. Before exercise training, the older subjects had a 47% lower HRV at rest compared with the young subjects (31 +/- 5 ms vs 58 +/- 4 ms, p = 0.0002). During peak exercise, the older subjects had less parasympathetic withdrawal than the young subjects (-45% vs -84%, p = 0.0001). Six months of intensive aerobic exercise training increased maximum oxygen consumption by 21% in the older group and 17% in the young group (analysis of variance: overall training effect, p = 0.0001; training effect in young vs old, p = NS). Training decreased the heart rate at rest in both the older (-9 beats/min) and the young groups (-5 beats/min, before vs after, p = 0.0001). Exercise training increased HRV at rest (p = 0.009) by 68% in the older subjects (31 +/- 5 ms to 52 +/- 8 ms) and by 17% in the young subjects (58 +/- 4 ms to 68 +/- 6 ms). Exercise training increases parasympathetic tone at rest in both the healthy older and young men, which may contribute to the reduction in mortality associated with regular exercise.
Abstract: BACKGROUND: Flow cytometry crossmatching is more sensitive than cytotoxic methods in identifying preformed antibodies to donor alloantigens. However, the significance of a positive flow crossmatch remains unknown for a recipient of a heart transplant who has a negative anti-human globulin crossmatch. METHODS: Flow crossmatching was performed retrospectively for 92 recipients of a primary cardiac allograft who underwent transplantation with a negative AHG crossmatch. RESULTS: Forty-six patients were flow crossmatch-positive for alloantibody: 20 were positive on both T and B lymphocytes, 12 were positive only on B lymphocytes, and 13 were positive only on T lymphocytes. Eleven had autoantibody invalidating the flow crossmatch with donor cells. Thirty-six patients had negative flow crossmatch. A significantly higher incidence of graft dysfunction with vascular rejection by 6 months was found for patients who had a positive flow crossmatch on B lymphocytes. This group also had an increased incidence of mortality within this same period. Patients who were flow crossmatch-positive on T and B lymphocytes were more likely to experience greater than two episodes of treated cellular rejection within the first 6 months. Flow crossmatch-positive patients stayed longer in the hospital in comparison to the other two groups, although the increases were not statistically significant. There were no differences between groups with regard to time to first rejection, absence of rejection episodes, episodes of decreased cardiac index (<2.3 L/m2), depressed left and right ventricular ejection fraction, or development of transplant atherosclerosis. CONCLUSION: A positive flow crossmatch identified a subset of patients who are predisposed to development of vascular rejection or are more likely to have frequent cellular rejection.
Abstract: A review of factors contributing to early mortality after cardiac transplantation revealed that up to 25% of deaths were due to primary graft dysfunction unrelated to rejection or infection. In light of this finding, evaluation of a donor heart with regard to its suitability for transplantation takes on added importance. In an effort to screen the suitability of donor hearts in the region covered by the Northwest Organ Procurement Agency (USA), all donors are evaluated by two-dimensional transthoracic echocardiography as part of the initial evaluation. A total of 110 donor echocardiograms were reviewed and an attempt was made to correlate the 30-day outcome with the parameters measured. An unexpected finding was that the presence of left ventricular hypertrophy in the donor heart was associated with an increase in the incidence of donor heart dysfunction compared with donors with normal echocardiographic profiles (33% vs 3%, P = 0.007).
Abstract: BACKGROUND: Exercise to exhaustion and infusions of isoproterenol and phenylephrine were used to study interactions between plasminogen activator regulation and the control of regional blood flow in 10 healthy males. METHODS AND RESULTS: Experimental measurements of cardiac output, heart rate, tissue plasminogen activator (TPA), urokinase plasminogen activator (UPA), plasminogen activator inhibitor (PAI-1), C1-inhibitor, and TPA/C1-inhibitor complex during the infusions and exercise were used to develop a comprehensive fluid-phase model of the circulatory regulation of fibrinolysis. alpha- and beta-adrenergic agonists increased TPA and UPA in plasma by different mechanisms: Phenylephrine decreased hepatic blood flow and thus clearance while isoproterenol stimulated increased secretion of TPA and UPA. Exercise to exhaustion increased TPA and UPA through a combination of increased secretion and decreased clearance. The time course of UPA and TPA release were similar, but the magnitude of their secretion responses differed. In vivo, C1-inhibitor bound to TPA at a rate of 553 mol-1.s-1. C1-inhibitor contributed equally with PAI-1 to TPA inhibition when active PAI-1 levels were low (20 to 50 pmol/L) but was less important when active PAI-1 levels were high. CONCLUSIONS: We conclude that secretion, inhibition, clearance, and regional blood flow effects must all be taken into account when evaluating changes in plasminogen activator levels.
Abstract: BACKGROUND: Cardiac aging alters many of the acute responses to exercise stress, but the extent to which chronic exercise (ie, training) can alter or improve the effects of aging in humans is largely unknown. METHODS AND RESULTS: Cardiovascular responses to graded supine exercise stress (beginning at 200 kpm and increasing by 200 kpm every 3 minutes till exhaustion) were assessed using radionuclide ventriculography in 13 older (age, 60 to 82 years) and 11 young (age, 24 to 32 years) rigorously screened healthy men before and after 6 months of endurance training. Repeated-measures ANOVA was used to test significance. During exercise, the old group had a lesser increase in heart rate (+105% old versus +166% young), a greater increase in mean blood pressure (+35% old versus +22% young), lesser increases in ejection fraction (+3 ejection fraction units old versus +11 units young) and peak ejection rate (+62% old versus +119% young), a greater increase in end-diastolic volume index (+8% old versus -10% young), a lesser fall in end-systolic volume index (-0% old versus -32% young), and a lesser increase in cardiac index (+135% old versus +189% young) (all P < .01 young/old versus exercise stage). Stroke volume index response to exercise was not different with aging (+14% old versus +6% young, P = NS). Exercise training increased maximal oxygen intake by 21% in the older group (28.9 +/- 4.6 to 35.1 +/- 3.8 mL.kg-1.min-1, P < .001) and by 17% in the young (44.5 +/- 5.1 to 52.1 +/- 6.3 mL.kg-1.min-1, P < .001) and increased peak workload by 24% in the old and 28% in the young. Exercise training had no differential effects on old versus young men. Among all subjects, training significantly reduced the resting heart rate by 12% (-8 beats per minute) and increased resting end-diastolic volume index by 13% (+9 mL/M2) and resting stroke volume index by 18% (+7 mL/M2) (all P < .01). At peak exercise, cardiac index increased by 16% (+1.07 L.M-2.min-1) compared with before training, which was the result of an increase in stroke volume of 18% (+7 mL/M2) (P < .001); peak heart rate was unchanged. The increase in stroke volume index at peak exercise was the result of both a 12% increase in end-diastolic volume index (+8 mL/M2) (P < .01) and an increase in ejection fraction (+3 ejection fraction units) (P < .05) at peak exercise. The increased ejection fraction at peak exercise occurred despite a 9% increase in systolic blood pressure (+18 mm Hg) (P < .01), suggesting an increase in contractility. Thus, both the young and old increased peak exercise cardiac output by use of the Frank-Starling mechanism (ie, cardiac dilatation) as well as an increase in ejection fraction. CONCLUSIONS: We conclude that there is an age-associated decline in heart rate, ejection fraction, and cardiac output responses to supine exercise in healthy men. Although the stroke volume responses of the young and old are similar, the old tend to augment stroke volume during exercise more through cardiac dilatation, with an increase in end-diastolic volume (+8%) but without much change in ejection fraction (+3 ejection fraction units), whereas the young rely more on an increase in the ejection fraction (+11 ejection fraction units) with no cardiac dilatation (-10%). Despite the significant cardiovascular changes that occur in the response to a single bout of exercise with aging, adaptations to chronic exercise training were not different with aging and included improvements in maximal workload and increases in ejection fraction, stroke volume index, and cardiac index at peak exercise.
Abstract: Reduced heart rate and contractile responses to beta-agonist stimulation characterize normal cardiac aging, but whether diastolic responses also decline with aging has not been determined in humans. Diastolic filling responses to isoproterenol were determined in 13 older (60-82 yr) and 11 young (24-32 yr) healthy men before and after endurance training. Filling rates were expressed in three ways: 1) normalized to end-diastolic volume per second, 2) normalized to stroke volume per second, and 3) as absolute milliliters of blood (ml.s-1.m-2). Peak early filling rates by all methods were reduced at rest and all isoproterenol doses with aging (all P < 0.0001 for old vs. young), whereas peak atrial filling rates were increased with aging. During isoproterenol, both peak early and peak atrial filling rates increased significantly (all P < 0.01); the increase in filling rates with isoproterenol was not different with aging (all NS for old vs. young x dose). Endurance training did not augment diastolic filling responses to isoproterenol. Although diastolic filling rates at rest are markedly altered by aging, diastolic filling responses to isoproterenol are not reduced with aging. Thus the age-associated declines in heart rate, ejection fraction, and cardiac output responses to beta-adrenergic stimulation with isoproterenol do not extend to diastolic filling responses.
Abstract: A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.
Abstract: BACKGROUND. Diastolic filling at rest is altered markedly with advancing age. Whether exercise training can improve diastolic filling at rest or during exercise in either healthy older or healthy young men has not been determined. The purpose of this study was to determine if 6 months of aerobic exercise training improves diastolic filling. METHODS AND RESULTS. Radionuclide diastolic filling parameters were measured at rest and during exercise in 14 older (age, 60 to 82 years) and 17 young (age, 24 to 32 years) rigorously screened healthy males before exercise training and in 13 older and 11 young men after 6 months of endurance exercise training. Diastolic filling rates were expressed in two ways, as absolute milliliters of blood (mL.s-1.m-2) and normalized to the end-diastolic volume. At baseline, the peak early filling rates were lower in the older group compared with the young group as expressed in absolute milliliters of blood (older, 85 +/- 7 mL.s-1.m-2; young, 173 +/- 10 mL.s-1.m-2; P < or = .0001) and in end-diastolic volume per second (1.66 +/- 0.11 versus 2.55 +/- 0.08, P < .0001), whereas the peak atrial filling rates were greater in absolute milliliters of blood (85 +/- 5 versus 56 +/- 7 mL.s-1.m-2, P = .003) and in end-diastolic volume per second (1.70 +/- 0.12 versus 0.80 +/- 0.06, P < .0001). During exercise, at any given heart rate, the older group had a lower peak filling rate than the young group. Also, at peak exercise, the single peak filling rate was decreased in the older group in mL.s-1.m-2 (384 +/- 19 versus 565 +/- 36 mL.s-1.m-2, P = .0002) and in end-diastolic volume per second (6.01 +/- 0.25 versus 7.91 +/- 0.28 end-diastolic volume per second, P < .0001). Six months of intensive aerobic exercise training had similar effects in the old and young groups overall. Maximal oxygen consumption increased 19% (ANOVA training effect, P < or = .0001) and echocardiographic left ventricular mass increased 8% (ANOVA training effect, P = .002). Training increased the resting peak early filling rate in absolute milliliters of blood by +14% (ANOVA training effect, P = .02). During exercise, the peak early or single peak filling rate at any given heart rate was increased. At peak exercise, the single peak filling rate was increased by 14% in mL.s-1.m-2 (ANOVA training effect, P = .0004). The only age-related differential effect of training was on the peak atrial filling rate in end-diastolic volume per second, which decreased by 27% in the older group but was unchanged in the young (+5%) (ANOVA young versus older, P = .001). The independent predictors of a greater maximal oxygen consumption by multivariate analysis were a higher peak exercise heart rate, a greater resting peak early filling rate, the exercise trained state, and a younger age. CONCLUSIONS. Healthy older men have reduced early diastolic filling at rest and during exercise compared with young men. Endurance exercise training enhances early diastolic filling at rest and during exercise in both the old and the young. Training reduces the elevated resting atrial filling rate in the old, whereas the young were unchanged. The training-induced augmentation of early diastolic filling at rest and during exercise may be an important adaptation to allow an increase in stroke volume at rest and an increase in stroke volume, cardiac output, and maximal oxygen consumption during exercise.
Abstract: The effects of region of interest (ROI) selection and correction for Compton-scattered photons using a buildup factor on radionuclide left ventricular volumes calculated by the Links method were compared in 19 humans with contrast ventriculography and in phantoms. Three different methods of ROI selection were compared: a manual ROI, a second derivative ROI and a 50% count-threshold ROI. In phantoms without Compton scatter correction, volumes were overestimated by 30% (manual ROI), 20% (derivative ROI) and 1% (count threshold ROI). In subjects, results without Compton scatter correction were similar with overestimates of 50% (manual ROI) and 20% (derivative ROI) and an underestimate by 3% (count threshold method). Correction for Compton-scattered photons with the use of a phantom-derived buildup factor resulted in improved accuracy for the manual ROI (+15%) and the derivative ROI (0%). A 50% count threshold ROI following interpolative background subtraction allows the accurate calculation of cardiac volumes without the need for scatter correction, while a second derivative ROI method requires a correction for Compton scatter with the use of a buildup factor.
Abstract: This study compared the accuracy and reproducibility of three previously described and one new radionuclide method of measuring left ventricular volumes in 19 subjects using contrast ventriculographic volumes (n = 38, mean volume = 126.6 ml) as the gold standard. The four methods were compared using both manual and automated ROIs. For manual ROIs, the Links (189.7 ml, r = 0.85), Starling (183.2 ml, r = 0.77) and the new count ratio method (141.4 ml, r = 0.90) overestimated contrast volumes, while the Massardo method (122.5 ml, r = 0.91) provided accurate volumes. For the automated ROIs, we performed an interpolative background subtraction and used a 50% threshold of the highest count pixel to define the ventricular regions. The automated Massardo method severely underestimated the contrast volume (59.5 ml, r = 0.90), while the other automated methods yielded accurate volumes: Links (122.4 ml, r = 0.89), Starling (118.1 ml, r = 0.81) and the new count ratio method (125.0 ml, r = 0.90). The interobserver reproducibility of the automated methods was excellent (mean difference = 1%-4%) compared to the manual methods (2%-8%). Because no additional images, blood counting, attenuation, or decay correction were necessary, the manual Massardo method and the automated count ratio method are the simplest to perform. We conclude that automated determination of left ventricular volumes using the new count ratio method is rapid, accurate, reproducible and could readily be incorporated into routine clinical use.
Abstract: To determine whether exercise-induced increases in tissue plasminogen activator (t-PA) were related to plasma epinephrine concentration during exercise, 14 healthy men (aged 24 to 62 years) were studied during epinephrine infusions (10, 25 and 50 ng/kg per min) and graded supine bicycle exercise, beginning at 33 W and increasing in 33-W increments until exhaustion. Plasma epinephrine, active and total t-PA, active plasminogen activator inhibitor type 1 (PAI-1) and t-PA/PAI-1 complex concentrations were measured at each exercise and infusion level. During epinephrine infusion, active and total t-PA levels increased linearly with the plasma epinephrine concentration (respective slopes [+/- SEM] of 0.062 +/- 0.003 and 0.076 +/- 0.003 pmol/ng epinephrine). During exercise, t-PA levels did not increase until plasma epinephrine levels increased, after which both active and total t-PA levels again increased linearly with the plasma epinephrine concentration, but at twice the rate observed with epinephrine infusion (0.131 +/- 0.005 and 0.147 +/- 0.005 pmol/ng, respectively). The t-PA level in blood was directly proportional to the plasma epinephrine concentration during both exercise and epinephrine infusion, suggesting that epinephrine release during exercise stimulates t-PA secretion. In these healthy subjects, active plasminogen activator inhibitor type 1 and t-PA/PAI-1 complex levels were low (41 +/- 11 and 21 +/- 5 pmol/liter, respectively) and did not change significantly during exercise or epinephrine infusion. It is concluded that approximately 50% of the increase in t-PA during exercise is due to stimulated release of t-PA by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: BACKGROUND. Cardiac aging is characterized by a reduced heart rate response to beta-agonist stimulation with isoproterenol, but whether the ejection fraction and other cardiovascular responses are reduced in humans is largely unknown. In addition, whether reduced beta-agonist responses can be improved with exercise training has not been determined in humans. METHODS AND RESULTS. Cardiovascular responses to graded isoproterenol infusions (3.5, 7, 14, and 35 ng/kg/min for 14 minutes each) were assessed in 15 older (age, 60-82 years) and 17 young (age, 24-32 years) rigorously screened healthy men. Thirteen older and 11 young subjects completed 6 months of endurance training and were retested. At baseline, the older group had reduced responses to isoproterenol for heart rate (+65% older versus +92% young, p less than 0.001), systolic blood pressure (+9% versus +24%, p less than 0.001), diastolic blood pressure (-12% versus -24%, p less than 0.05), ejection fraction (+12 versus +20 ejection fraction units, p less than 0.001), and cardiac output (+70% versus +100%, p less than 0.001). The mean plasma isoproterenol concentrations achieved during the infusions were marginally higher (p = 0.07) in the older group (128 +/- 58, 227 +/- 64, 354 +/- 114, and 700 +/- 125 pg/ml) than in the young (79 +/- 20, 178 +/- 49, 273 +/- 79, and 571 +/- 139 pg/ml). Intensive training increased maximal oxygen consumption by 21% in the older group (28.9 +/- 4.6 to 35.1 +/- 3.8 ml/kg/min, p less than 0.001) and by 17% in the young (44.5 +/- 5.1 to 52.1 +/- 6.3 ml/kg/min, p less than 0.001), but training did not augment any of the cardiovascular responses to isoproterenol in either group. The mean plasma isoproterenol concentrations at the four infusion doses were unchanged after training in both groups. CONCLUSIONS. We conclude that there is an age-associated decline in heart rate, blood pressure, ejection fraction, and cardiac output responses to beta-adrenergic stimulation with isoproterenol in healthy men. Altered beta-adrenergic responses probably contribute to the reduced cardiac responses to maximal exercise that also occur with aging. Furthermore, intensive exercise training does not increase cardiac responses to beta-adrenergic stimulation with isoproterenol in either young or older men. The reduced beta-adrenergic response appears to be a primary age-associated change that is not caused by disease or inactivity.
Abstract: Most radionuclide methods for measuring cardiac volume require a determination of the blood radioactivity concentration. Thus, changes in blood radioactivity over time or during interventions might lead to spurious volume estimates unless blood radioactivity is serially measured. The effects of elevated epinephrine, posture and exercise on 99mTc-labeled blood radioactivity concentration were studied in 15 young (mean age = 28 yr) and 14 older (mean age = 68 yr) healthy males. An epinephrine infusion of 50 ng/kg/min resulted in a 4.1% +/- 1.0% increase in 99mTc-blood radioactivity (p less than or equal to 0.001) compared to baseline. Sitting increased blood radioactivity concentration by 12.3% +/- 3.0% (p less than 0.0002) compared to the supine position and peak supine bicycle exercise caused an 11.0% +/- 1.7% increase (p less than or equal to 0.0001) compared to supine rest. There was a significantly greater increase during peak supine exercise in the young compared to the older subjects (15.0% +/- 2.3% versus 6.3% +/- 2.0%, p less than or equal to 0.01). The mechanism of the increase in blood radioactivity concentration is uncertain, but presumably reflects the addition of hemoconcentrated red blood cells from the spleen and/or the loss of plasma volume. Failure to correct for the increased blood radioactivity concentration during exercise or pharmacological interventions will result in a significant error in serial measurements of cardiac volumes by methods requiring RBC radioactivity measurements.
Abstract: BACKGROUND. The effects of 6 months of intensive endurance exercise training on resting tissue-type plasminogen activator (t-PA) activity, plasminogen activator inhibitor type 1 (PAI-1) activity, t-PA antigen, and fibrinogen were studied in 10 young (24-30 years) and in 13 old male subjects (60-82 years). METHODS AND RESULTS. After training, maximum oxygen consumption was increased in the young group by 18% (44.9 +/- 5.0 to 52.9 +/- 6.6 ml/kg/min, p less than 0.001), whereas it was increased in the old group by 22% (29.0 +/- 4.2 to 35.5 +/- 3.6 ml/kg/min, p less than 0.001). The young group had no significant changes in any of the measured variables, whereas the old group had a 39% increase in t-PA activity (0.82 +/- 0.47 to 1.14 +/- 0.42 IU/ml, p less than 0.03), a 141% increase in the percentage of t-PA in the active form (11.1 +/- 7.7 to 26.8 +/- 15.1%, p less than 0.01), a 58% decrease in PAI-1 activity (8.4 +/- 4.9 to 3.5 +/- 1.7 AU/ml, p less than 0.01), and a 13% decrease in fibrinogen (3.57 +/- 0.79 to 3.11 +/- 0.52 g/l, p less than 0.01). CONCLUSIONS. We conclude that intensive exercise training enhances resting t-PA activity and reduces fibrinogen and PAI-1 activity in older men. These effects are potential mechanisms by which habitual physical activity might reduce the risk of cardiovascular disease.
Abstract: A new analytical technique (consensus analysis) was devised to assess the performance of laboratory tests that are commonly used to monitor the acute and chronic phases of inflammatory disease. On thirty-one tests carried out monthly for 7 months in seventeen patients with rheumatoid arthritis, the consensus analysis procedure ranked plasma viscosity and erythrocyte sedimentation rate in a tie for first place. Measurement of the acute-phase serum protein orosomucoid ranked third. Consensus analysis has the potential to reduce laboratory costs by identifying the most useful tests; it also promises to be helpful in the design of new laboratory tests that are more sensitive and specific.
Abstract: Patient red blood cell (RBC) index means, when used in quality control, form an independent standard that is as accurate and precise as preserved blood controls. If such patient data are routinely incorporated in intralaboratory and interlaboratory quality control programs, a substantial improvement in the present state-of-the-art is possible. Within the laboratory, each method serves to confirm the adequacy of the other. In interlaboratory control trials the combination makes it possible to specify the cause of most misanalyses. For similar reasons, the combination of both methods enables the manufacturer of quality control material to assess the adequacy of the manufacturing and value assignation process.
Abstract: A comparison of the Bull's algorithm (XB) for quality control with a system based on analysis of preserved blood suggested that the preserved blood approach was the more sensitive method. However, the procedures compared were not equivalent. Four control blood samples analyzed by a multirule Shewhart approach were compared with a single XB result. Consequently, a reexamination of the relative sensitivities of the two methods was undertaken with a multirule Shewhart approach applied to both methods. On this basis, both methods have equivalent sensitivity. Once the XB mean reflects the shifted mean (and at all times with a drifting mean), either the XB algorithm or the analysis of preserved blood will detect systematic errors with similar probability using similar control rules.
