Altered purine nucleotide degradation during exercise in patients with essential hypertension

Purine degradation occurs during strenuous muscle exercise and plasma levels of hypoxanthine (HX), purine degradation intermediate, increase. Purine nucleotide degradation has not been investigated in patients with essential hypertension (HTN). The present study determined whether purine nucleotide degradation is altered in patients with HTN. Cardiopulmonary exercise test was performed with serial measurements in blood lactate and plasma HX in 24 patients (14 men and 10 women) with essential HTN (World Health Organization [WHO] class I to II; mean age, 57.7 +/- 2.1 years) and 24 age-, sex-matched normal subjects. Exercise was terminated either by severe fatigue or excess blood pressure increase. Peak work rate (WR) (normal v HTN, 151 +/- 10 v 135 +/- 8 W, not significant [NS]) was not different, but peak oxygen uptake (peak Vo(2), 26.3 +/- 1.5 v 22.2 +/- 0.9 mL/min/kg, P <.05) and anaerobic threshold were lower in patients with HTN. Resting levels of blood lactate and plasma HX were similar, but the increment from rest to peak exercise (Delta) for lactate (Delta lactate: 4.4 +/- 0.4 v 3.4 +/- 0.4 mmol/L, P <.05) and for HX (Delta HX, 15.9 +/- 2.2 v 9.1 +/- 1.1 micromol/L, P <.05) were significantly smaller in patients with HTN. When normalized by the peak WR, Delta HX/peak WR (0.105 +/- 0.013 v 0.069 +/- 0.007 micromol/L/W, P <.05) was significantly lower in patients with HTN. Patients with HTN exhibited reduced HX response to exercise with impaired exercise capacity. The exercise-induced changes in plasma HX were smaller in patients with HT when normalized with peak WR. These results suggest that the purine nucleotide degradation is reduced in patients with HTN.     

Catabolism of adenine nucleotides favors adenosine production following exercise in patients with chronic heart failure

BackgroundAdenosine 5′-triphosphate is catabolized to adenosine 5′-monophosphate (AMP), which is further degraded by 2 pathways: deamination to inosine 5′-monophosphate and ammonia by AMP deaminase, or dephosphorylation to adenosine and inorganic phosphate by 5′-nucleotidase. Because adenosine is believed to be cardioprotective and we have reported that ammonia production decreased after exercise in patients with chronic heart failure (CHF), we determined if plasma adenosine levels after exercise increases in patients with CHF.Methods and ResultsMaximal ergometer exercise tests with expired gas analysis were performed in 51 patients with CHF (age = 61 ± 2 years, New York Heart Association [NYHA] class I/II/III = 19/18/14) and 20 age-matched normal controls. Serial changes in both plasma ammonia and adenosine levels were determined. The ratio for Δammonia to peak work rate became smaller (control, NYHA I/II/III: 0.59 ± 0.13/0.41 ± 0.06/0.37 ± 0.10/0.22 ± 0.11 μg/dL·watts, respectively) and the ratio for Δadenosine to peak work rate was significantly higher in class III CHF (control, NYHA I/II/III: 0.93 ± 0.21/0.86 ± 0.14/1.11 ± 0.27/2.92 ± 0.67 nmol/L·watts, respectively).ConclusionIn patients with CHF after exercise, the plasma levels of adenosine increased along with the decrease in the plasma levels of ammonia. Considering the physiologic cardioprotective actions of adenosine, the enhanced adenosine production after exercise may be an important adaptive response in patients with CHF.     

Abnormalities of skeletal muscle metabolism in patients with chronic heart failure: evidence that they are present at rest.

OBJECTIVE: To investigate abnormalities of skeletal muscle metabolism in patients with congestive heart failure. SETTING: A university teaching hospital. METHODS: 43 patients (22 New York Heart Association (NYHA) grade II, 21 grade III) and 10 controls were studied. A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction (MVC) was measured using handgrip dynamometry. Subjects performed handgrip exercise, 5 s contraction followed by 5 s rest for 5 min at 25%, 50%, and 75% of MVC or until exhaustion. Blood was taken at rest and 0 and 2 min after exercise for measurement of lactate and ammonia. After 30 min the procedure was repeated with fixed workloads of 7 kg, 14 kg, and 21 kg. RESULTS: MVC (kg, mean (SEM)) was lower in patients than in controls (control 42.45 (2.3); NYHA II 34.13 (1.3), P = 0.003; NYHA III 33.13 (1.94), P = 0.008). Resting lactate (mmol/l) was higher in patients than controls (control 0.65 (0.06); NYHA II 0.84 (0.08), P = 0.13; NYHA III 1.18 (0.1), P = 0.002). Resting ammonia (mumol/l) was higher in NYHA III (65.7 (6.0)) than in NYHA II (48.0 (3.7), P = 0.016); no difference was found between controls (48.0 (7.1)) and patients. The overall lactate and ammonia response to exercise was greater in NYHA III than in NYHA II and controls (P < 0.05). At volitional exhaustion, peak lactate (mmol/l: NYHA III 3.31 (0.26); NYHA II 2.56 (0.16); controls 2.71 (0.22); P = 0.022 NYHA III v NYHA II) and ammonia (mumol/l: NYHA III) 126.4 (8.97); NYHA II 92.9 (7.23); controls 109 (16.3); P = 0.006 NYHA III v NYHA II) were higher in severe congestive heart failure. CONCLUSIONS: Skeletal muscle metabolism is abnormal at rest in congestive heart failure. During exercise, the degree of metabolic abnormality is related to the symptomatic status of the patient.     

Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, and patients with chronic heart failure (CHF) are reported to have high plasma ET-1 levels. The aim of this study was to investigate the relation between plasma ET-1 levels and clinical correlates in patients with CHF. The effects of maximal exercise on plasma ET-1 levels were also investigated. METHODS: Plasma concentrations of ET-1, norepinephrine, and atrial and brain natriuretic peptide (ANP and BNP) both at rest and after maximal cardiopulmonary exercise test were determined in 100 patients with CHF (60 +/- 12 years, New York Heart Association [NYHA] class I-III, left ventricular ejection fraction [LVEF]=36 +/- 8%, peak oxygen uptake [VO2] = 18.2 +/- 5.0 mL/min/kg) and 27 controls. RESULTS: Patients with NYHA class II and III CHF had higher ET-1 levels (controls, NYHA class I, II, III: 2.1 +/- 0.6, 2.1 +/- 1.0, 2.6 +/- 0.9, 3.4 +/- 0.8 pg/mL, analysis of variance P <.0001). Maximal exercise did not alter ET-1 levels in controls or in each CHF subgroup. When all CHF patients were analyzed together, cardiothoracic ratio (P<.01), peak VO2 (P<.001), plasma norepinephrine (P<.01), plasma ANP (P<.01), and plasma BNP (P<.001) were significantly related with resting ET-1 levels on univariate analysis. Multivariate analysis revealed peak VO2 and plasma BNP levels showed an independent and significant relationship with the resting plasma ET-1 levels. CONCLUSIONS: Resting ET-1 levels were increased in symptomatic patients with CHF, and maximal exercise did not increase ET-1 levels. Peak VO2 and plasma BNP levels were independently associated with resting plasma ET-1 levels in patients with CHF.     

Ammonia response to exercise in patients with congestive heart failure.

OBJECTIVE: To assess energy depletion in skeletal muscle in patients with congestive heart failure by measuring blood purine metabolites during exercise and, at the same time, determine the implications of the ammonia response to exercise in these patients. SETTING: Tottori University Hospital, Yonago, Japan. PATIENTS: 49 heart failure patients (New York Heart Association (NYHA) grades I-III) and 16 normal subjects. MAIN OUTCOME MEASURES: Blood lactate, ammonia, and hypoxanthine levels were measured during exercise with expired gas analysis. RESULTS: In normal exercising subjects as well as in each heart failure subgroup, the ammonia threshold was significantly higher than both the lactate threshold [control: 21.8 (SD 5.3) v 17.4 (3.3) ml/kg/min; NYHA class I: 18.9 (3.8) v 15.5 (2.6); class II: 14.8 (2.5) v 12.7 (2.4); class III: 13.5 (2.6) v 11.8 (2.5)] and the ventilatory threshold (P < 0.01). The difference between the ammonia and lactate thresholds was noted in all normal subjects and in all heart failure patients. The ammonia threshold, however, was significantly lower in heart failure patients than in normal subjects and it decreased with increasing NYHA class (P < 0.01). Maximum ammonia levels were lower in the heart failure group and decreased further with higher NYHA classifications [control: 198 (52) mg/dl; NYHA class I: 170 (74); class II: 134 (58); class III: 72 (15); P < 0.01]. There were significant correlations between maximum ammonia values and maximum lactate, oxygen consumption, and hypoxanthine levels (r = 0.74, 0.48, and 0.87, respectively; P < 0.001). CONCLUSIONS: The ammonia threshold may reflect the onset of ATP depletion in exercising skeletal muscles, as opposed to the onset of anaerobic respiration. It seems therefore that energy depletion in skeletal muscles during exercise occurs after attaining the anaerobic threshold. Both aerobic and anaerobic capacities of skeletal muscle are reduced in patients with congestive heart failure.     

Anaerobic metabolism as an indicator of aerobic function during exercise in cardiac patients.

To determine whether patients with heart disease depend more than normal subjects on anaerobic metabolism to perform the same level of exercise, the anaerobic threshold, slope of the increase in carbon dioxide output with respect to oxygen uptake (delta VCO2/delta VO2) and the slope of the increase in oxygen uptake with respect to the increase in work rate (delta VO2/delta WR) both below and above the anaerobic threshold during exercise were evaluated. A total of 106 patients with chronic heart disease and 42 healthy subjects performed a symptom-limited incremental exercise test in a ramp pattern on a cycle ergometer. Peak oxygen uptake was significantly lower in the patients with heart disease than in the normal subjects. The anaerobic threshold, which was 20 +/- 4.6 ml/min per kg in normal subjects, decreased significantly with progressing severity of functional class: 16 +/- 2.4, 14.1 +/- 2.5 and 11.3 +/- 1.5 ml/min per kg, respectively, in patients in class I, class II and class III. The slope of delta VO2/delta WR, which represents the degree of aerobic metabolism, was also decreased both below and above the anaerobic threshold with increasing severity of heart disease. delta VCO2/delta VO2 below the anaerobic threshold was approximately 0.9 (p = NS between normal subjects and patients). However, delta VCO2/delta VO2 above the anaerobic threshold became steeper with increasing severity of heart disease: 1.37 +/- 0.17 in normal subjects versus 1.55 +/- 0.24, 1.67 +/- 0.3 and 1.8 +/- 0.35 respectively, in patients in functional class I, class II and class III.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced chronotropic reserve to the metabolic requirement during exercise in advanced heart failure with old myocardial infarction

We studied the metabolic and cardiac responses to exercise by expiratory gas analysis in 40 patients with old myocardial infarction and 33 normal sedentary males. On the basis of exercise energy metabolism, the elevation of the respiratory quotient (RQ; RQ = VCO2/VO2) during exercise is caused by the increase of blood lactate due to the augmented anaerobic metabolism. Functional aerobic impairment (FAI) in our study was significantly advanced in the control group and the NYHA functional class I, class II and class III groups, that is, -2.3 +/- 11.2%, +14.8 +/- 10.4%, +27.8 +/- 13.8% and +49.4 +/- 2.8%, respectively. The delta RQ values were similar among all groups; 0.29 respectively. The delta RQ values were similar among all groups; 0.29 +/- 0.06, 0.28 +/- 0.07, 0.27 +/- 0.07 and 0.29 +/- 0.09, respectively. Functional chronotropic impairment (FCI) for the same groups was -0.9 +/- 7.0%, +1.4 6.1%, +3.8 +/- 4.8% and +8.7 +/- 6.0%, and that of the class III group was significantly larger than that of the control group. Thus, in the class III congestive heart failure group, the chronotropic response to the metabolic requirement was impaired in comparison to the control group. It was concluded that the reduced chronotropic reserve was present in NYHA class III patients with old myocardial infarction, and that this mechanism might contribute to a decrease in the pump reserve of the heart, resulting in further impairment of physical capacity in these patients.     

Sympathetic nervous system response to exercise in patients with congestive heart failure

The response of the sympathetic nervous system to exercise in patients with congestive heart failure was studied in 65 patients (NYHA functional class I 28, II 23, and III 14) and 22 normal subjects (N) by submaximal treadmill testing with the modified Bruce's or Sheffield's protocols. Plasma norepinephrine (NE) and epinephrine (E) levels were also measured at rest, at the end of each stage, and immediately after and 5 min after exercise. In accordance with the severity by NYHA functional class, the exercise duration became shorter and the discontinuation of exercise with symptoms occurred more frequently. Systolic blood pressure and double products (DP) at the peak exercise were significantly lower in patients with NYHA class III. NE and increments of NE increased during exercise [peak NE (pg/ml); N: 589, I: 646, II: 1253, and III: 997] and were higher at rest, during exercise and in recovery in patients with NYHA classes II and III than in the normal subjects and NYHA class I patients. E increased gradually during exercise [peak E (pg/ml); N: 60, I: 66, II: 63, and III: 66] and there were no significant differences among the four groups. A negative correlation (r = -0.53) between the peak NE and exercise duration was observed in normal subjects, while a positive correlation (r = 0.55) was observed in patients with NYHA class II. A positive correlation (r = 0.54) between DP at the peak exercise and the peak NE was observed in patients with NYHA class I, whereas a negative correlation (r = -0.46) was observed in patients with NYHA class III. The NE response in patients with NYHA classes II and III increased significantly, suggesting compensatory activation of the sympathetic nervous system for impaired cardiac function. In conclusion, the NE response to submaximal exercise testing differs in each NYHA functional class and it might be a useful indicator to evaluate cardiac function of patients with congestive heart failure.     

Treating heart failure with enhanced external counterpulsation (EECP): design of the Prospective Evaluation of EECP in Heart Failure (PEECH) trial

BACKGROUND: Enhanced external counterpulsation (EECP) treatment can improve exercise tolerance in patients with ischemic heart disease; however, the possible benefits of EECP in patients with stable heart failure (HF) and left ventricular dysfunction (LVD) are unclear. An open pilot study showed significant increases in exercise tolerance in HF patients undergoing EECP. Thus a larger, controlled study of EECP in patients with stable HF (New York Heart Association [NYHA] classes II and III) and LVD was undertaken. METHODS AND RESULTS: The PEECH trial is a controlled, randomized, single-blind, parallel-group, multicenter study of 187 patients with symptomatic but stable HF (NYHA classes II and III) and an LV ejection fraction < or =35% was designed to assess the efficiency of EECP in patients with stable HF. Medical therapy is optimized in all patients based on the recommendations of the Heart Failure Society of America ("Usual Care"), and then randomized between 2 treatment groups; UC or EECP (35 hours over 7 weeks). CONCLUSION: Efficacy measures include standard exercise tolerance tests on a treadmill (modified Naughton protocol), with measurements of peak oxygen uptake and exercise duration time; quality of life questionnaires; NYHA classification; and neurohormonal markers of HF.     

Urocortin 2 infusion in human heart failure.

AIMS: To document the haemodynamic, neurohormonal, and renal responses to Urocortin 2 (UCN2) infused in human heart failure (HF). METHODS AND RESULTS: Eight male patients with HF [left ventricular ejection fraction (LVEF) < 40%, NYHA class II-III] received placebo and 25 [low dose (LD)] and 100 microg [high dose (HD)] of UCN2 intravenously over 1 h in a single-blind, placebo-controlled, dose-escalation design. UCN2 increased cardiac output (CO) (mean peak increments +/- SEM; placebo 0.3 +/- 0.1; LD 1.0 +/- 0.3; HD 2.0 +/- 0.2 L/min; P < 0.001) and LVEF (0.0 +/- 1.5; LD 5.9 +/- 2.1; HD 14.1 +/- 2.7%; P = 0.001) and decreased mean arterial pressure (placebo 6.7 +/- 1.3; LD 11.4 +/- 1.7; HD 19.4 +/- 3.3 mmHg; P = 0.001), systemic vascular resistance (SVR) (placebo 104 +/- 37; LD 281 +/- 64; HD 476 +/- 79 dynes s/cm(5); P < 0.003), and cardiac work (CW) (placebo 48 +/- 12; LD 66 +/- 22; HD 94 +/- 13 mmHg/L/min; P < 0.001). No significant effect on vasoconstrictor/volume-retaining neurohormones was noted. UCN2 decreased urinary volume (P = 0.035) but not creatinine excretion (P = 0.962). CONCLUSION: Intravenous UCN2 in HF induced increases in CO and LVEF with falls in SVR and CW. No hormone response occurred. The role of UCN2 in circulatory regulation and its potential therapeutic application in heart disease warrant further investigation.     

Abnormal heart rate recovery immediately after cardiopulmonary exercise testing in heart failure patients

An attenuated heart rate recovery (HRR) immediately after exercise has been shown to be predictive of mortality. It is not known whether HRR predicts mortality when measured in patients with heart failure. The present study was undertaken to evaluate the ability of HRR to predict mortality in patients with heart failure. We studied 84 NYHA class II or III chronic congestive heart failure patients who had a left ventricular ejection fraction < or = 40%. All patients underwent symptom limited cardiopulmonary exercise testing. The value for the HRR was defined as the difference in heart rate between peak exercise and one-minute later; a value < or = 18 beats per minute was considered abnormal. The patients were divided into 2 groups according to the value of HRR. Those with abnormal HRR were assigned to group I and those with normal HRR were assigned to group II. The 2 groups were compared with each other regarding baseline characteristics and exercise capacity assessed by peak VO2. There were 26 patients (31%) in group I and 58 patients (69%) in group II. Group II patients had better performance on treadmill exercise testing than group I patients. They had greater exercise duration (7.5 +/- 3.8 minutes versus 5 +/- 3.5 minutes, P = 0.006), better heart-rate reserve (79 +/- 25% versus 63 +/- 27%, P = 0.01), and higher values of maximal heart-rate (141 +/- 18 beats/min versus 132 +/- 17 beats/min, P = 0.04). Group II patients also had higher peak VO2 values (16.8 +/- 4.4 mL/kg/min versus 14.4 +/- 3.6 mL/kg/min, P = 0.01). When we separated the groups according to beta-blocker usage, beta-blockers had no prominent effect on HRR. In the follow-up period (mean 14.1 +/- 6.1 months), the presence of abnormal HRR and lower peak VO2 (< or = 14 mL/kg/min) were the only significant predictors of mortality in our patient population (adjusted hazard ratio [HR] 5.2, 95% CI, 1.3 to 24, P = 0.03 and adjusted HR 13, 95% CI, 2.1 to 25.6, P = 0.005, respectively). It seems that the attenuated HRR value one minute after peak exercise appears to be a reliable index of the severity of exercise intolerance in heart failure patients and this study supports the value of HRR as a prognostic marker among heart failure patients referred for cardiopulmonary exercise testing for prediction of prognosis.     

Significance of end-tidal P(CO(2)) response to exercise and its relation to functional capacity in patients with chronic heart failure

OBJECTIVES: The value of end-tidal PCO(2) monitoring during exercise in patients with chronic heart failure has not been elucidated. The present study was designed to examine end-tidal PCO(2) response to exercise and its relation to functional capacity in patients with chronic heart failure. METHODS AND RESULTS: Maximal upright ergometer exercise with respiratory gas analysis and arterial blood gas analysis were performed in 105 patients with chronic heart failure (34 patients in New York Heart Association [NYHA] class I, 38 patients in NYHA class II, and 33 patients in NYHA class III) and 14 normal control subjects. Peak O(2) uptake, excessive exercise ventilation as assessed by the slope of the relation between expired minute ventilation and CO(2) output (VE-VCO(2)), and the ratio of physiologic dead space to tidal volume (VD/VT) were determined. Cardiac output was also measured during exercise in 28 patients with chronic heart failure. Arterial PO(2) or PCO(2) values at rest and during exercise were not different among the four groups. However, end-tidal PCO(2) was significantly lower, and arterial to end-tidal PCO(2) difference and VD/VT were significantly higher in NYHA class III patients than other groups during exercise. The maximal end-tidal PCO(2) during exercise was significantly reduced as the severity of chronic heart failure advanced (45.7 +/- 4.0 mm Hg in normal control subjects, 43.5 +/- 4.8 mm Hg in NYHA class I patients, 39.7 +/- 5.1 mm Hg in NYHA class II patients, and 34.9 +/- 5.3 mm Hg in NYHA class III patients). The maximal end-tidal PCO(2) during exercise was significantly correlated with peak O(2) uptake (r = 0.68; p < 0.001) and maximal cardiac index (r = 0.73; p < 0.001), and inversely related to Ve-VCO(2) (r = - 0.84; p < 0.001) and VD/VT at peak exercise (r = -0.65; p < 0.001). CONCLUSIONS: The decreased end-tidal PCO(2) during exercise, which is caused by high ventilation/perfusion ratio mismatching, reflects both reduced cardiac output response to exercise and increased exercise ventilation due to enlarged physiologic dead space in advanced chronic heart failure. The end-tidal PCO(2) during exercise can be used to evaluate the functional capacity of patients with chronic heart failure.     

Severity and pathophysiology of heart failure on the basis of anaerobic threshold (AT) and related parameters

Cardio-pulmonary exercise testing was performed in 99 normal subjects and 382 patients with cardiac disease in order to evaluate anaerobic threshold (AT) and related parameters as indices for assessing the severity of heart failure. AT could be determined easily during ergometer exercise testing with ramp protocol by monitoring minute ventilation (VE), oxygen uptake (VO2) and carbon dioxide output (VCO2). Peak VO2 and the ratio of VO2 rising to work rate increment (delta VO2/delta WR) were also determined. There was good correlation between the AT determined by respiratory measurement and that determined by arterial lactic acid concentration (r = 0.93, n = 15). The reproducibility of AT was excellent between 2 testings with a 3-hour interval. AT (ml/min/kg) and peak VO2 (ml/min/kg) declined with age, and males showed higher values than females in both indices. %AT, determined by the predicted AT values of each age and sex, decreased as NYHA class progressed as follows: 90.2 +/- 15.4% in class I, 76.9 +/- 13.8% in class II, and 59.7 +/- 11.9% in class III. Although delta VO2/delta WR was not influenced by age or sex, it also decreased as the severity of heart disease progressed. These results suggest that indices from cardiopulmonary exercise testing, especially AT, are closely related to the pathophysiology of heart failure, so that they are objective and reliable parameters for evaluation of the severity of heart failure and are sensitive enough to detect the efficacy of therapeutic intervention for heart failure.     

Soluble TNF-alpha and interleukin-6 receptors in the urine of heart failure patients. Their clinical value and relationship with plasma levels

BACKGROUND: Proinflammatory cytokines are important mediators in heart failure (HF). Recently, urinary levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been determined. AIMS: The purpose of this study was to measure the urinary levels of TNF-alpha and IL-6 receptors, sTNF-RI, sTNF-RII, sIL-6R, and the relationship with plasma levels and NYHA classes in HF. METHODS: Plasma and urine were collected from 114 HF patients and sTNF-RI, sTNF-RII and sIL-6R (ng/ml) were analyzed. RESULTS: For the whole population, plasma levels of sTNF-RI were 2.1+/-0.1, of sTNF-RII were 5.0+/-0.3 and of sIL-6R were 49.8+/-2.5. Urinary levels were: sTNF-RI, 2.8+/-0.5, r=0.5, p<0.001; sTNF-RII, 12.6+/-2.1, r=0.4, p<0.001; and sIL-6R, 4.2+/-0.4, NS. In NYHA III subjects, we found sTNF-RI, r=0.6, p<0.01, sTNF-RII, r=0.5, p<0.05, and sILR-6, r=0.5, p<0.05. Both plasma TNF receptors and urinary levels of sTNF-RII were higher in patients in a more severe NYHA class (p<0.05). CONCLUSIONS: Urine is a good environment to study sTNF-RI and sTNF-RII, and this fact has diagnostic and prognostic implications. Plasma and urinary levels of TNF receptors showed a fair correlation, which was increased in higher NYHA classes. Plasma and urinary levels of sIL6R showed a good correlation in NYHA III. The TNF receptor levels in urine increased in patients with more severe HF.     

A pilot experience with permanent biventricular pacing to treat advanced heart failure

BACKGROUND: The prognosis and quality of life of patients with advanced heart failure remain poor. The purpose of this study was to evaluate new nonpharmacologic approaches. Biventricular pacing was proposed in this indication, based on the encouraging results of acute hemodynamics studies. METHODS: Fifty patients with drug-resistant heart failure (New York Heart Association [NYHA] class III/IV, 16 of 34) were consecutively implanted with biventricular pacemakers. All patients had severe dilated cardiomyopathy and intraventricular conduction delay. Survival, NYHA class, electrocardiogram, echocardiographic data, and exercise tolerance were assessed over a mean follow-up period of 15.4 +/- 10. 2 months. RESULTS: At the end of follow-up, 55% of patients were alive without heart transplantation or left ventricular assistance device. The mortality rate was significantly lower in class III (12. 5%) than in class IV patients (52.5%). In survivors, biventricular pacing significantly improved symptoms (NYHA class 2.2 +/- 0.5 at follow-up vs 3.7 +/- 0.5 at baseline) and exercise tolerance ((. )VO(2) peak 15.5 +/- 3.4 mL/min per kilogram at follow-up vs 11.1 +/- 3 mL/min per kilogram at baseline). CONCLUSIONS: Biventricular pacing appears to improve the functional status of patients with dilated cardiomyopathy with advanced heart failure. The technique appears to be attractive as an additive treatment, especially in class III patients. Controlled randomized studies are needed to validate this novel concept.     

Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure

BACKGROUND: Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels. AIM: To investigate the effects of carvedilol on the heart rate response to exercise and oxidative stress in patients with CHF. METHODS AND RESULTS: Thirty stable NYHA classes II-III CHF patients received carvedilol therapy for 6 months, at a mean maintenance dose of 25 mg (range 6.25-50 mg/day). After treatment, the patients showed a significant improvement in their functional NYHA class (p=0.013), increased left ventricular ejection fraction (LVEF) (24+/-1.4% to 31+/-2.3%, p=0.003) and 6-min walk distance (499+/-18 to 534+/-18 m, p=0.03), without changes in the peak VO2. At baseline, norepinephrine (NE) plasma levels increased with exercise (510+/-51 to 2513+/-230 pg/mL, p<0.001), and these levels were not affected by carvedilol. Chronotropic responsiveness index (increase in heart rate divided by the increase in NE from rest to peak exercise) was not changed by carvedilol (0.049+/-0.001 to 0.042+/-0.001, p=0.6). MDA levels of CHF patients decreased after treatment with carvedilol (2.4+/-0.2 to 1.1+/-0.2 microM, p<0.001), without changes in antioxidant enzyme activities. CONCLUSIONS: Carvedilol treatment in patients with CHF results in reduced oxidative stress without restoration of the chronotropic responsiveness index.     

Urinary biopyrrins levels are elevated in relation to severity of heart failure

OBJECTIVES: We investigated the relationship between the urinary levels of biopyrrins and the severity of heart failure (HF). BACKGROUND: Oxidative stress is evident in heart disease and contributes to the development of ventricular dysfunction in patients with HF. Biopyrrins, oxidative metabolites of bilirubin, have been discovered as potential markers of oxidative stress. METHODS: We measured the levels of urinary biopyrrins and plasma B-type natriuretic peptide (BNP) in 94 patients with HF (59 men; mean age 65 years) and 47 control subjects (30 men; mean age 65 years). Urine and blood samples were taken after admission in all subjects. Further urine samples were obtained from 40 patients after treatment of HF. RESULTS: The urinary biopyrrins/creatinine levels (micromol/g creatinine) were the highest in patients in New York Heart Association (NYHA) class III/IV (n = 26; 17.05 [range 7.85 to 42.91]). The urinary biopyrrins/creatinine levels in patients in NYHA class I (n = 35; 3.46 [range 2.60 to 5.42]) or II (n = 33; 5.39 [range 3.37 to 9.36]) were significantly higher than those in controls (2.38 [range 1.57 to 3.15]). There were significant differences in urinary biopyrrins/creatinine levels among each group. The treatment of HF significantly decreased both urinary biopyrrins/creatinine levels (from 7.43 [range 3.84 to 17.05] to 3.07 [range 2.21 to 5.71]) and NYHA class (from 2.5 +/- 0.1 to 1.7 +/- 0.1). Log biopyrrins/creatinine levels were positively correlated with log BNP levels (r = 0.650, p < 0.001). CONCLUSIONS: These results indicate that urinary biopyrrins levels are increased in patients with HF and are elevated in proportion to its severity.     

A propensity matched study of New York Heart Association class and natural history end points in heart failure

The association between higher New York Heart Association (NYHA) functional class and poor outcome in heart failure (HF) is well known. However, to what extent these associations are confounded by covariates such as age, the severity of disease, and co-morbidity burden is unknown. In the Digitalis Investigation Group (DIG) trial, 2,441 of the 7,788 patients with chronic HF had NYHA class III or IV symptoms. Propensity scores for NYHA classes III and IV were calculated for each patient and were then used to match 1,863 patients in NYHA classes III and IV with 1,863 patients in NYHA classes I and II. Kaplan-Meier and matched Cox regression analyses were used to estimate associations of NYHA class III or IV with mortality and hospitalizations during a median of 37 months of follow-up. Compared with 34% (641 of 1,863) patients in NYHA classes I and II (mortality rate 1,175 in 10,000 person-years of follow-up), 42% (777 of 1,863) patients in NYHA classes III and IV (mortality rate 1,505 in 10,000 person-years) died from all causes (hazard ratio 1.29, 95% confidence interval [CI] 1.14 to 1.45, p <0.0001). Hospitalizations due to all causes occurred in 66% (1,232 of 1,863) patients in NYHA classes I and II (hospitalization rate 3,898 in 10,000 person-years) and 71% (1,322 of 1,863) patients in NYHA classes III and IV (hospitalization rate 4,793 in 10,000 person-years) (hazard ratio 1.16, 95% CI 1.05 to 1.28, p = 0.003). The hazard ratios for patients in NYHA classes III and IV, compared with those for those in NYHA classes I and II, for other outcomes were 1.29 for cardiovascular mortality (95% CI 1.12 to 1.48, p <0.0001), 1.49 for HF mortality (95% CI 1.20 to 1.84, p <0.0001), 1.18 for cardiovascular hospitalization (95% CI 1.06 to 1.32, p = 0.002), and 1.17 for HF hospitalization (95% CI 1.03 to 1.34, p = 0.017). In conclusion, baseline NYHA class is a marker of hospitalization, disease progression, and mortality in a wide spectrum of ambulatory patients with chronic HF.     

The role of exercise ventilation in clinical evaluation and risk stratification in patients with chronic heart failure

BACKGROUND: Patients with chronic heart failure (CHF) are characterised by an increased ventilatory response to exercise. The role of exercise ventilation in the risk stratification and evaluation of patients with CHF has not yet been established. AIM: To examine the relationship between exercise ventilation indices and clinical parameters of CHF and to assess the prognostic value of the ventilatory response to exercise. METHODS: The study group consisted of 87 patients with CHF (72 males, mean age 58 years) with a mean left ventricular ejection fraction of 32%. Ten patients were in NYHA class I, 38 - in NYHA class II, 34 - in NYHA class III, and 5 - in NYHA class IV. The control group consisted of 20 patients without CHF (13 males, mean age 58 years, mean LVEF - 61%). All studied subjects underwent maximal exercise test with gas-exchange measurement. The following parameters were analysed: peak exercise oxygen consumption [peak VO(2) (ml/kg/min)], VE-VCO(2) index [a coefficient of linear regression analysis depicting an association between ventilation (VE) and carbon dioxide production (VCO(2)) during exercise] and VE/VCO(2) ratio at peak exercise to VE/VCO(2) ratio while at rest (VE/VCO(2 peak/rest)). RESULTS: Ventilatory response indices were significantly higher in patients with CHF compared with controls: VE-VCO(2) - 37.9+/-11.1 vs 27.1+/-4.1; VE-VCO(2 peak/rest) - 0.89+/-0.14 vs 0.75+/-0.10 (p<0.001). In CHF patients a significant positive correlation between ventilatory response parameters and NYHA class (VE-VCO(2) - r=0.52; VE/VCO(2 peak/rest) - r=0.47) and a negative correlation with peak VO(2) (VE-VCO(2) - r=-0.52; VE/VCO(2 peak/rest) - r=-0.49) were noted (p<0.0001 for all correlations). No correlation was found between ventilatory parameters and echocardiographic variables or CHF aetiology. During the follow-up period lasting at least 12 months, 17 (22%) patients died. In the univariate Cox model, NYHA class III-IV, decreased peak VO(2) and increased VE-VCO(2) and VE/VCO(2 peak/rest) values were significantly associated with the risk of death. The multivariate analysis revealed that VE/VCO(2 peak/rest) > or =1.0 was the adverse prognostic factor, independent of peak VO(2) (p=0.02) and NYHA class (p=0.01). The Kaplan-Meier analysis showed that prognosis during the 18-month follow-up period in patients with enhanced exercise ventilation was worse than in the remaining patients (59% survival in patients with VE/VCO(2 peak/rest) > or =1.0 59% vs 91% survival in patients with VE/VCO(2 peak/rest) <1.0, p=0.001). CONCLUSIONS: In patients with stable CHF simple exercise ventilation parameters may provide important clinical and prognostic information.     

Heart rate recovery--a potential marker of clinical outcomes in heart failure patients receiving beta-blocker therapy

BACKGROUND: Heart rate recovery (HRR) within the first few minutes of graded exercise has been associated with impaired clinical outcomes in patients being evaluated for coronary artery disease. HRR is abnormal in patients with heart failure (HF), but has not been associated with clinical outcomes in these patients. The objective of the present study was to determine whether HRR following cardiopulmonary exercise testing (CPET) correlates with peak oxygen consumption (VO(2)), and whether it impacts clinical outcomes, including HF hospitalizations and total mortality, or the need for cardiac transplantation. METHODS: CPET was performed in 78 patients referred to the Montreal Heart Institute (Montreal, Quebec) with congestive HF between January 2000 and December 2002. All patients had New York Heart Association class II or III HF with a left ventricular ejection fraction of 45% or lower. Mean (+/- SD) age was 53+/-11 years and left ventricular ejection fraction was 27+/-9%. Forty-four per cent had ischemic cardiomyopathy, 88% received beta-blockers and 79% received angiotensin-converting enzyme inhibitors. HRR was defined as the difference from peak exercise HR to HR measured at specific time intervals. HRR was calculated 30 s, 60 s, 90 s and 120 s after exercise. RESULTS: Mean peak VO(2) was 18.0+/-5.3 mL/kg/min, resting HR was 74+/-13 beats/min and peak HR was 119+/-22 beats/min. HRR measured was 10+/-9 beats/min after 30 s, 20+/-12 beats/min after 60 s, 25+/-15 beats/min after 90 s and 30+/-13 beats/min after 120 s. At 90 s, patients with an HRR below 24 beats/min were more likely to have an HF hospitalization at five-year follow-up (eight hospitalizations [22.2%] versus two hospitalizations [2.7%]; P=0.0134). There was a correlation between peak VO(2) and HRR 90 s and 120 s after completion of the exercise test (r=0.40 after 90 s, P=0.001, and r=0.41 after 120 s, P=0.008). CONCLUSIONS: In patients with HF, blunted HRR 90 s and 120 s after CPET correlate with peak VO(2) and are associated with increased risk of worsening HF. HRR is easily measured and a useful marker for morbidity in patients with HF.