Cardiopulmonary Baroreflex Control of Renal Sympathetic Nerve Activity Is Impaired in Dogs With Left Ventricular Dysfunction.

BACKGROUND: Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state. METHODS: LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ΔRR/Δsystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs. RESULTS: Cardiopulmonary baroreflex sensitivity (slope of %ΔRNA/ΔPCWP) for mild LVD (-17.8%/mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P < .05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing. CONCLUSIONS: Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase.

Proinflammatory cytokine activation is linked to apoptotic mediator, soluble Fas level in patients with chronic heart failure.

The Fas/Fas Ligand system is a major apoptosis signaling pathway that is up-regulated in patients with chronic heart failure (CHF). Serum soluble Fas (sFas) levels increase in proportion to the CHF severity and may have prognostic value, therefore, sFas is a promising biomarker of heart failure. In this study, we attempted to identify the determinants of sFas levels in patients with CHF. Serum levels of tumor necrosis factor (TNF)-α and its soluble receptors (sTNF-R1 & sTNF-R2), interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), glycoprotein (gp)130, and sFas were measured in 106 patients with CHF and 39 controls. All subjects performed a symptom-limited cycle ergometer exercise test with expired gas analysis. CHF patients had higher levels of TNF-α, sTNF-R1, sTNF-R2, IL-6, and gp130. Serum levels of sFas (controls versus CHF; 2.60 ± 0.88 versus 3.38 ± 1.23 ng/mL, P = 0.0004) were higher in CHF. On univariate analysis, age (P = 0.0003), NYHA functional class (P = 0.0012), peak VO2 (P < 0.0001), plasma norepinephrine (P = 0.0013), log IL-6 (P < 0.0001), log TNF-α (P = 0.0002), log sTNF-R1 (P < 0.0001), and log TNF-R2 (P < 0.0001) were significantly related to log sFas levels. Multivariate analysis showed that age and log IL-6 and log sTNF-R1 levels were independently associated with log sFas levels (overall R = 0.603, P < 0.0001). Serum levels of sFas were increased in patients with CHF, and age and serum IL-6 and sTNF-R1 levels were independent determinants of sFas levels. These data suggest that proinflammatory cytokine activation is linked to the Fas/Fas Ligand system in patients with CHF.

A case of atrial tachycardia sensitive to increased caffeine intake.

A 33-year-old Japanese man with atrial tachycardia visited our clinic. He regularly consumed daily alcohol with cola, one cup of regular coffee, and a candy containing 0.7 mg of caffeine per tablet. After stopping his caffeine intake, his arrhythmia ameliorated. Since caffeine might be associated with his arrhythmia, a caffeine load test (equivalent to his daily intake of caffeine) was performed for 4 days. Atrial tachycardia time from a Holter recording was 44.2 minute/day before the caffeine load, compared with 215.2 minute/day during the caffeine load. Plasma caffeine concentration before and during caffeine loading was 3.1 mg/dL and 5.4 mg/dL, respectively. Caffeine use seemed to be an important factor for his atrial tachycardia, since his arrhythmia became worse during caffeine load testing and was ameliorated after the cessation of caffeine.

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

BACKGROUND: Adenosine 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 RESULTS: Maximal 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 delta ammonia 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 microg/dL x watts, respectively) and the ratio for delta adenosine 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 x watts, respectively). CONCLUSION: In 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.

Status of endothelial dependent vasodilation in patients with hyperuricemia.

Hyperuricemia has been associated with an increased risk for cardiovascular disease and increased mortality. However, the biologic mechanisms that link elevated serum uric acid to cardiovascular disease are uncertain. This study tested the hypothesis that elevated serum uric acid is associated with impaired endothelial function in hyperuricemic patients without any overt cardiovascular disease. Seventeen male patients with hyperuricemia (mean age 42+/-4 years) and 9 control subjects (mean age 45+/-5 years) were studied. All subjects were nonsmokers. All patients had never been treated for hyperuricemia, were on no medications, and were free of any other known diseases. Endothelial function was evaluated by flow-mediated dilation measured by ultrasound. Flow-mediated dilation was significantly impaired in patients with hyperuricemia (4.0+/-0.7%) compared with control subjects (6.4+/-0.8%) (p=0.044). Flow-mediated dilation correlated inversely with uric acid levels (r=-0.4, p=0.05). Nitrate-induced dilation was 12.3+/-1.0% in patients with hyperuricemia and 11.8+/-2.3% in control subjects (p=0.82). Impaired endothelial-dependent vasodilation is present in hyperuricemic patients even in the absence of any overt cardiovascular disease. The elevated serum uric acid, per se, may constitute a novel risk factor for endothelial dysfunction.

Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure.

PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.

Effectiveness of a novel serotonin blocker, sarpogrelate, for patients with angina pectoris.

BACKGROUND: We have recently demonstrated that a single oral administration of sarpogrelate, a 5-HT(2A) receptor antagonist, may improve exercise capacity in anginal patients with well-developed collaterals. The aim of the current study was to investigate the effectiveness of 2-week treatment with sarpogrelate on anginal symptoms and exercise capacity in anginal patients. METHODS: A treadmill exercise test was repeated after a 2-week period with or without sarpogrelate (100 mg 3 times a day) in 20 patients with angiographically proven stable angina. Anginal symptoms and daily physical activity by the specific activity scale (SAS) were also evaluated. RESULTS: Treatment with sarpogrelate significantly increased the SAS score and prolonged exercise time to the onset of 0.1-mV ST depression. When data were analyzed in a subgroup of patients (n = 8) with well-developed collaterals, the treatment with sarpogrelate decreased the number of anginal attacks (control vs sarpogrelate, 3.0 +/- 2.8 vs 0.9 +/- 1.1/2 weeks, P <.05), increased the SAS score (5.2 +/- 1.6 vs 6.2 +/- 1.3 METS, P <.05), and increased the time to the onset of 0.1-mV ST depression (235 +/- 84 vs 295 +/- 127 seconds, P <.05). In addition, the double product at the onset of 0.1-mV ST depression increased by 15% (P <.05) after sarpogrelate. In contrast, all parameters were not significantly changed after sarpogrelate treatment in patients (n = 12) without well-developed collaterals. CONCLUSIONS: These findings indicate the therapeutic effectiveness of sarpogrelate for anginal patients, especially for patients with well-developed collaterals.

Interleukin-6 and tumor necrosis factor-alpha levels increase in response to maximal exercise in patients with chronic heart failure.

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. Strenuous exercise causes activation of both systems but the effect of acute bouts of exercise on cytokines is not known in patients with CHF. This study determined whether maximal exercise induces activation of cytokines in CHF. Plasma interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, epinephrine, norepinephrine, and atrial and brain natriuretic peptides (ANP and BNP) were determined before and after symptom-limited cardiopulmonary exercise testing in 80 patients with CHF (LVEF=38+/-1%, peak VO(2)=18.8+/-0.5 ml/min/kg) and age-matched 33 controls. Resting IL-6 (Controls vs. CHF: 1.3+/-0.2 vs. 2.5+/-0.3 pg/ml, P<0.001) and TNF-alpha (2.7+/-0.2 vs. 3.8+/-0.2 pg/ml, P<0.01) were elevated in CHF. LogIL-6 and logTNF-alpha were positively correlated (r=0.34 and r=0.35, respectively) with logplasma norepinephrine, and were negatively correlated (r=-0.39 and r=-0.32, respectively) with peak VO(2). Maximal exercise increased IL-6 and TNF-alpha both in controls and CHF (all P<0.01). Changes in IL-6 (DeltaIL-6) correlated with Deltaepinephrine (r=0.63, P<0.0001) and Deltanorepinephrine (r=0.57, P=0.0006) in controls, but not in CHF. DeltaTNF-alpha correlated with DeltaANP (r=0.28, P=0.01) only in CHF. In summary, cytokine activation at rest was associated with high plasma norepinephrine and exercise intolerance. Maximal exercise caused increases in IL-6 and TNF-alpha concentrations. Sympathetic activation seems to be important for the IL-6 increase during exercise in controls. In CHF, changes in ANP during exercise were associated with the exercise-induced increase in TNF-alpha, but still unknown mechanisms are involved for the cytokine activation during exercise.

Characteristics of cardiac myxoma with constitutional signs: a multicenter study in Japan.

BACKGROUND: A relationship between constitutional signs in patients with cardiac myxoma and interleukin-6 has been noted. However, there is little information about characteristics of cardiac myxomas associated with constitutional signs. HYPOTHESIS: The objective of this study was to clarify the characteristics of myxoma patients who had constitutional signs. METHODS: Questionnaires were sent to cardiology or cardiovascular surgery divisions at university hospitals throughout Japan. Constitutional signs were considered present when a patient had fever, weight loss, or elevations of C-reactive protein or gammaglobulin. In addition, interleukin-6 concentrations were evaluated in some patients. RESULTS: Data were obtained in 249 patients with primary cardiac tumors (204 myxomas, 15 other primary benign tumors, and 30 primary malignant tumors), confirmed histologically between 1993 and 1996. Fever and weight loss were observed in 15 and 6% of patients with myxoma, respectively, while C-reactive protein and gammaglobulin were increased in 39 and 21%, respectively. This amounted to a prevalence of constitutional signs in 49%. All constitutional signs disappeared after tumor resection. Age, gender, tumor site, and frequency of thrombosis did not differ between patients with and without constitutional signs. Tumors associated with constitutional signs were significantly more likely to be large, multiple, or recurrent than those unassociated with constitutional signs. CONCLUSIONS: Constitutional signs are present in about half of patients with myxoma. Large or multicentric tumors are likely to induce constitutional signs, which are reversible upon resection. These might suggest that constitutional signs result when interleukin-6 concentrations exceed a certain threshold.

Effects of angiotensin II type 1 receptor antagonist, losartan, on ventilatory response to exercise and neurohormonal profiles in patients with chronic heart failure.

Chronic heart failure (CHF) is associated with abnormal neurohormonal profiles and increased ventilatory response to exercise. This study determined if treatment with angiotensin II type 1 receptor antagonist, losartan, improves ventilatory efficiency and neurohormonal factors in patients with CHF. Symptom-limited cardiopulmonary exercise testing was performed after a 2-week placebo period (baseline) and after 16 weeks of treatment with losartan (40 +/- 4 mg/day) in 10 patients with CHF (age 57.7 +/- 3.7 years). Echocardiogram, daily physical activity (by the specific activity scale), and neurohormones were evaluated. Treatment with losartan increased left ventricular ejection fraction (baseline vs. losartan: 31 +/- 3 vs. 39 +/- 3%, p<0.01) and specific activity scale score (5.3 +/- 0.5 vs. 6.4 +/- 0.4 METS, p<0.05). Losartan decreased the ventilatory response to carbon dioxide production during exercise (VE/VCO2 slope: 34.6 +/- 2.4 vs. 32.0 +/- 2.2, p<0.05). Plasma brain natriuretic peptide concentrations were decreased after therapy (301 +/- 79 vs. 176 +/- 53 pg/ml, p<0.05). In summary, the results of this open-label, uncontrolled study suggest that chronic treatment with losartan may improve ventilatory efficiency and decrease plasma brain natriuretic peptide concentrations with the improvement of physical activity and left ventricular systolic function in patients with CHF.

Excessive purine degradation during semi-ischemic forearm test in patients with diabetes mellitus.

OBJECTIVE: The aim of this study was to investigate whether or not the purine degradation in the skeletal muscle during forearm exercise is augmented in patients with diabetes mellitus (DM). METHODS: We used the semi-ischemic forearm test to examine the release of lactate (deltaLAC), ammonia (deltaAmm) and hypoxanthine (deltaHX) before exercise, 0, 4, 10, and 60 minutes after exercise in eleven diabetic patients and seven normal controls. RESULTS: The sum of the increased HX (DM vs Controls: 26.1 +/- 21.2 vs 7.8 +/- 5.9 micromol/L, p < 0.05) was greater in diabetic patients. When patients were divided into the excessive response group (n = 7) and normal response group (n = 4), the maximum increments in deltaHX and deltaAmm in the excessive response group (16.8 +/- 3.2 micromol/l and 122 +/- 60 micromol/l) were greater (p < 0.05) than those in the control group (3.6 +/- 3.0 micromol/l and 32 +/- 34 micromol/l and the normal response group (2.9 +/- 2.9 micromol/l and 27.4 +/- 12.7 micromol/l). DeltaLAC both in the excessive response group (5.4 +/- 1.5 mmol/l) and the normal response group (3.6 +/- 1.0 mmol/l) were higher (p < 0.05) than that of the control group (1.7 +/- 0.5 mmol/l). The prevalence of diabetic retinopathy was higher in the excessive response group than in the normal response group (75% vs. 25%). CONCLUSION: These data suggest that patients with DM, especially with microangiopathy have augmented purine degradation during the semi-ischemic forearm test. Factors responsible for the augmented purine degradation in these patients remain to be determined.

Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study.

BACKGROUND: Hyperuricemia is common in chronic heart failure (CHF), and it is a strong independent marker of prognosis. Upregulated xanthine oxidase (XO) activity and impaired renal excretion have been shown to account for increased serum uric acid (UA) levels in CHF. Therapeutic interventions with allopurinol to reduce UA levels by XO inhibition have been shown to be beneficial. Discussions are ongoing whether UA itself is actively involved or it is a mere marker of upregulated XO activity within CHF pathophysiology. Therefore, the aim of this study was to test the effect of lowering UA by uricosuric treatment without XO inhibition on hemodynamic and metabolic characteristics of CHF. Impaired renal excretion of UA was taken into account. METHODS AND RESULTS: Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (Cl(UA)) were measured in 82 patients with CHF. SUA was significantly increased compared with controls of similar age (control, 5.45+/-0.70 mg/dL; New York Heart Association I, 6.48+/-1.70 mg/dL; New York Heart Association II, 7.34+/-1.94 mg/dL; New York Heart Association III, 7.61+/-2.11 mg/dL; P<0.01). Patients with CHF showed lower uUA excretion and Cl(UA). On multivariate analysis, insulin, brain natriuretic peptide (P<0.01), and creatinine levels (P=0.05) showed independent correlation with SUA. The treatment effect of the uricosuric agent benzbromarone was tested in 14 patients with CHF with hyperuricemia in a double-blind, placebo-controlled, randomized crossover study design. Benzbromarone significantly decreased SUA (P<0.01). Brain natriuretic peptide, left ventricular ejection fraction, and dimensions in echocardiographic assessment did not change after benzbromarone therapy. In contrast, fasting insulin (placebo, 18.8+/-8.9 microU/mL; benzbromarone, 11.0+/-6.2 microU/mL; P<0.05), homeostasis model assessment of insulin resistance index (placebo, 5.4+/-2.6; benzbromarone, 3.0+/-1.7; P<0.05), and tumor necrosis factor-alpha (placebo, 2.59+/-0.63 pg/mL; benzbromarone, 2.14+/-0.51 pg/mL; P<0.05) improved after benzbromarone, and the changes in tumor necrosis factor-alpha levels were correlated with reduction of SUA (P<0.05). CONCLUSIONS: These results show that UA lowering without XO inhibition may not have an effect on hemodynamic impairment in CHF pathophysiology. To the extent that these data are correct, this finding suggests that upregulated XO activity rather than UA itself is actively involved in hemodynamic impairment in CHF. Clinical Trial Registration- clinical trials.gov. Identifier: NCT00422318.

Comparative effects of amlodipine monotherapy and combination therapy with betaxolol on cardiac autonomic nervous activity and health-related quality of life in patients with poorly controlled hypertension.

BACKGROUND: The aim of the study was to evaluate whether the combined treatment of calcium channel blocker, amlodipine and beta-blocker, betaxolol, favorably affects cardiac autonomic nervous activity (CANA) and health-related quality of life (HRQL). METHODS AND RESULTS: A total of 65 patients with a poor blood pressure (BP) control with a low dose amlodipine therapy were randomly assigned to the amlodipine dose-up group (n=21) and betaxolol adding group (n=44). Before and after a 6-month treatment, BP, heart rate variability (HRV), HRQL and blood chemistries were evaluated. Low frequency (LF) spectra/high frequency (HF) spectra and HF/total power spectra (TP) were calculated as indexes of CANA, and HRQL was assessed by the questionnaire sheets. BP was well controlled in all patients of the present study. In the betaxolol adding group, LF/HF decreased (2.1+/-1.9 to 1.3+/-0.9, p<0.05) and HF/TP reciprocally increased (0.41+/-0.17 to 0.52+/-0.18, p<0.05), whereas the amlodipine dose-up group showed no significant changes in the HRV. HRQL was significantly improved in the betaxolol adding group, whereas it remained unchanged in the amlodipine dose-up group. Blood chemistries remained unchanged except for the slightly increased plasma brain natriuretic peptide concentrations in the betaxolol adding group (36+/-47 to 62+/-62 pg/ml, p<0.05). CONCLUSIONS: Combined treatment of amlodipine and betaxolol appears to be more useful than amlodipine dose-up therapy, because combined treatment improves CANA and HRQL.

Neurohormonal determinants of peak oxygen uptake in patients with chronic heart failure.

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. This study determined whether peak oxygen uptake (VO2) can be predicted by the degree of neurohormonal and cytokine activations in CHF. Plasma norepinephrine. epinephrine, renin-angiotensin system activity, ANP, BNP, and serum interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha were measured in 84 CHF patients (age, 59 +/- 1 years, LVEF, 36 +/- 1%) and 34 controls. Maximal cardiopulmonary exercise testing was performed. Peak VO2 (Controls vs CHF: 27.8 +/- 1.3 vs 18.2 +/- 0.5 mL/min/kg, P < 0.0001) was lower in CHF. Patients with CHF had increased plasma norepinephrine (211 +/- 11 vs 315 +/- 24 pg/mL), renin activity (1.2 +/- 0.2 vs 6.2 +/- 1.1 ng/mL/hr), ANP (22 +/- 3 vs 72 +/- 7 pg/mL), and BNP levels (18 +/- 3 vs 200 +/- 25 pg/mL) (all P < 0.01). Serum IL-6 (1.1 0.1 vs 2.4 +/- 0.3 pg/mL) and TNF-alpha (2.7 +/- 0.2 vs 4.0 +/- 0.3 pg/mL) levels were higher in CHF (both P < 0.001). Univariate analysis revealed that age (P < 0.001), cardiothoracic ratio (P < 0.001), norepinephrine (P < 0.0001), ANP (P < 0.001), BNP (P < 0.01), and log IL-6 (P < 0.05) were significantly related with peak VO2. Stepwise regression analysis indicated that plasma norepinephrine and ANP emerged as significant determinants of peak VO2, independent of patient age (overall R = 0.61, P < 0.0001). In summary, patients with CHF exhibited activation of neurohormones and proinflammatory cytokines. Among the elevated hormonal and cytokine markers, plasma norepinephrine and ANP levels were independent predictors of exercise capacity.

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.

Transient left ventricular apical ballooning in a patient with bicuspid aortic valve created a left ventricular thrombus leading to acute renal infarction.

A 44-year-old woman had tako-tsubo-like ventricular dysfunction with chest pain and ST segment elevation on the ECG. Echocardiography revealed a bicuspid aortic valve with moderate to severe aortic regurgitation. She developed mild heart failure during the clinical course, but the medication (furosemide, enalapril, and asprin) had to be stopped because of skin eruptions. Four weeks after ceasing the antiplatelet agent, she was re-admitted with acute renal infarction. Enhanced chest computed tomography revealed a filling defect in the left ventricle and echocardiography showed a high echogenic mass in the left ventricular apical wall. These findings strongly suggested that the renal infarction was caused by an embolism derived from a left ventricular thrombus that formed during the clinical course of the transient left ventricular apical ballooning. Anticoagulation therapy with urokinase and warfarin successfully lysed the thrombus. Left ventricular thrombus should be considered a complication of transient left ventricular apical ballooning, especially in patients with organic heart disease.

Effects of the angiotensin-converting enzyme inhibitor alacepril on exercise capacity and neurohormonal factors in patients with mild-to-moderate heart failure.

1. Alacepril is a long-acting, sulphydryl-containing angiotensin-converting enzyme inhibitor. Data are limited regarding the effects of alacepril on exercise tolerance in patients with chronic heart failure (CHF). The aim of the present study was to determine the effects of chronic alacepril treatment on exercise capacity and neurohormones in patients with CHF. 2. The effects of 12 weeks treatment with alacepril on clinical, echocardiographic and cardiopulmonary exercise variables were studied in 18 CHF patients (mean age: 63 +/- 2 years; New York Heart Association (NYHA) class I n = 6, class II n = 10, class III n = 2) in a cross-over fashion. Resting levels of plasma noradrenaline, renin-angiotensin system activity and natriuretic peptides were evaluated. 3. Treatment with alacepril significantly improved NYHA functional class and decreased cardiothoracic ratio (60.1 +/- 2.0 vs 58.1 +/- 1.9% for baseline vs alacepril, respectively; P < 0.01). Cardiac dimensions by echocardiogram were decreased after alacepril therapy. Peak Vo2 (17.7 +/- 1.2 vs 19.5 +/- 1.3 mL/min per kg; P < 0.01) and anaerobic threshold (11.7 +/- 0.6 vs 13.2 +/- 0.9 mL/min per kg; P < 0.01) increased with alacepril treatment. Plasma noradrenaline and plasma angiotensin II levels were not altered, but plasma aldosterone (77.7 +/- 13.5 vs 51.7 +/- 9.7 pg/mL; P < 0.01), atrial natriuretic peptide (ANP; 86.5 +/- 20.3 vs 43.6 +/- 7.6 pg/mL; P < 0.05) and brain natriuretic peptide (BNP; 222.7 +/- 59.3 vs 117.7 +/- 34.3 pg/mL; P < 0.05) levels decreased after alacepril treatment. 4. These results suggest that treatment with alacepril improves functional status and exercise capacity in patients with mild-to-moderate CHF. Neurohormones were favourably influenced by alacepril therapy, with significant decreases in plasma aldosterone, ANP and BNP levels.

Prognostic significance of exercise plasma noradrenaline levels for cardiac death in patients with mild heart failure.

The present study was designed to determine whether exercise plasma noradrenaline (NA) levels could predict cardiac death in patients with mild heart failure in whom the plasma NA levels were only minimally elevated. Treadmill exercise testing with serial measurement of plasma NA and plasma adrenaline were performed in 142 patients with heart failure (New York Heart Association class I-II; age, 58+/-12 years) and 26 age-matched normal subjects. During a median follow-up of 9.6 years, 27 cardiac deaths occurred among the patients. By univariate Cox proportional hazard analysis, left ventricular end-systolic dimension (p<0.001), age (p<0.01), peak exercise heart rate (p<0.01), exercise plasma NA level (p<0.01) and left ventricular ejection fraction (p<0.001) were identified as significant prognostic markers. In a multivariate analysis, exercise plasma NA level was identified as the most powerful prognostic marker (p<0.001), followed by left ventricular end-systolic dimension and peak exercise heart rate. In addition, from the Kaplan-Meier analysis, patients with a supramedian level of exercise plasma NA concentration (NA > or =840pg/ml) had a significantly lower survival rate than those with an inframedian level (p<0.01). Exercise plasma NA levels can provide prognostic information in patients with mild heart failure, which suggests an important role of exercise-induced activation of sympathetic nervous system activity in the prognosis of patients with mild heart failure.