Tuan Peng Chua

Hormonal Changes and Catabolic/Anabolic Imbalance in Chronic Heart Failure and Their Importance for Cardiac Cachexia

BACKGROUND The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure. METHODS AND RESULTS Healthy control subjects (n=16) and patients with chronic heart failure (CHF), classified clinically as cachectic (8% to 35% weight loss over > or = 6 months before study, n=16) or noncachectic (n=37), were assessed for markers of disease severity (maximal oxygen consumption, left ventricular ejection fraction, NYHA functional class). These markers were compared with plasma concentrations of potentially important anabolic and catabolic factors. The degree of neurohormonal activation and catabolic/anabolic imbalance was closely related to wasting but not to conventional measures of the severity of heart failure. Compared with control subjects and noncachectic patients, cachectic patients had reduced plasma sodium and increased norepinephrine, epinephrine (all P<.0001), cortisol, tumor necrosis factor (TNF)-alpha (both P<.002), and human growth hormone (P<.05). Insulin-like growth factor-1, testosterone, and estrogen were similar in all groups. Insulin was increased only in the noncachectic patients (P<.005 versus control subjects). Dehydroepiandrosterone was reduced in the cachectic patients (P<.02 versus control subjects). Insulin, cortisol, TNF-alpha, and norepinephrine correlated independently with wasting in CHF (P<.05; multiple regression of these four factors versus percent ideal weight, R2=.50, P<.0001). CONCLUSIONS Cachexia is more closely associated with hormonal changes in CHF than conventional measures of the severity of CHF. This study suggests that the syndrome of heart failure progresses to cardiac cachexia if the normal metabolic balance between catabolism and anabolism is altered.

Clinical Correlates and Prognostic Significance of the Ventilatory Response to Exercise in Chronic Heart Failure

OBJECTIVES This study sought to investigate the clinical characteristics of patients with chronic heart failure and an increased ventilatory response to exercise and to examine the prognostic usefulness of this response. BACKGROUND The ventilatory response to exercise is increased in many patients with chronic heart failure and may be characterized by the regression slope relating minute ventilation to carbon dioxide output (VE-VCO2 slope) during exercise. METHODS One hundred seventy-three consecutive patients (155 men; mean [+/-SD] age 59.8 +/- 11.5 years; radionuclide left ventricular ejection fraction [LVEF] 28.4 +/- 14.6%) underwent cardiopulmonary exercise testing (peak oxygen consumption 18.5 +/- 7.3 ml/kg per min; VE-CO2 slope 34.8 +/- 10.6) over a 2-year period. Using 1.96 standard deviations above the mean VE-VCO2 slope of 68 healthy age-matched subjects (mean slope 26.3 +/- 4.1), we defined a high ventilatory response to exercise as a slope >34. RESULTS Eighty-three patients (48%) had an increased VE-VCO2 slope (mean 43.1 +/- 8.9). There was a difference in age (62.2 vs. 57.3 years, p = 0.005), New York Heart Association functional class (2.9 vs. 2.1, p < 0.001), LVEF (24.7 vs. 31.9%, p = 0.0016), peak oxygen consumption (14.9 vs. 21.7 ml/kg per min, p < 0.0001) and radiographic cardiothoracic ratio (0.58 vs. 0.55, p = 0.002) between these patients and those with a normal slope. In the univariate Cox proportional hazards model, the E-VCO2 slope was an important prognostic factor (p < 0.0001). In the multivariate Cox analyses using several variables (age, peak oxygen consumption, VE-VCO2 slope and LVEF), the VE-VCO2 slope gave additional prognostic information (p = 0.018) beyond peak oxygen consumption (p = 0.022). Kaplan-Meier survival curves at 18 months demonstrated a survival rate of 95% in patients with a normal VE-VCO2 slope compared with 69% in those with a high slope (p < 0.0001). CONCLUSIONS A high VE-VCO2 slope selects patients with more severe heart failure and is an independent prognostic marker. The VE-VCO2 slope may be used as a supplementary index in the assessment of patients with chronic heart failure.

Depressed Heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

After acute myocardial infarction, depressed heart rate variability (HRV) has been proven to be a powerful independent predictor of a poor outcome. Although patients with chronic congestive heart failure (CHF) have also markedly impaired HRV, the prognostic value of HRV analysis in these patients remains unknown. The aim of this study was to investigate whether HRV parameters could predict survival in 102 consecutive patients with moderate to severe CHF (90 men, mean age 58 years, New York Heart Association [NYHA] class II to IV, CHF due to idiopathic dilated cardiomyopathy in 24 patients and ischemic heart disease in 78 patients, ejection fraction [EF], 26%; peak oxygen consumption, 16.9 ml/kg/min) after exclusion of patients in atrial fibrilation with diabetes or with chronic renal failure. In the prognostic analysis (Cox proportional-hazards model, Kaplan-Meier survival analysis), the following factors were investigated: age, CHF etiology, NYHA class, EF, peak oxygen consumption, presence of ventricular tachycardia on Holter monitoring, and HRV measures derived from 24-hour electrocardiography monitoring, calculated in the time (standard deviation of all normal RR intervals [SDNN], standard deviation of 5-minute RR intervals [SDANN], mean of all 5-minute standard deviations of RR intervals [SD], root-mean-square of difference of successive RR intervals [rMSSD], and percentage of adjacent RR intervals >50 ms different [pNN50]) and frequency domain (total power [TP], power within low-frequency band [LF], and power within high-frequency band [HF]). During follow-up of 584 +/- 405 days (365 days in all who survived), 19 patients (19%) died (mean time to death: 307 +/- 315 days, range 3 to 989). Coxs univariate analysis identified the following factors to be predictors of death: NYHA (p = 0.003), peak oxygen consumption (p = 0.01), EF (p = 0.02), ventricular tachycardia on Holter monitoring (p = 0.05), and among HRV measures: SDNN (p = 0.004), SDANN (p = 0.003), SD (p = 0.02), and LF (p = 0.003). In multivariate analysis, HRV parameters (SDNN, SDANN, LF) were found to predict survival independently of NYHA functional class, EF, peak oxygen consumption, and ventricular tachycardia on Holter monitoring. The Kaplan-Meier survival curves revealed SDNN < 100 ms to be a useful risk factor; 1-year survival in patients with SDNN < 100 ms was 78% when compared with 95% in those with SDNN > 100 ms (p = 0.008). The coexistence of SDNN < 100 ms and a peak oxygen consumption < 14 ml/kg/min allowed identification of a group of 18 patients with a particularly poor prognosis (1-year survival 63% vs 94% in the remaining patients, p <0.001). We conclude that depressed HRV on 24-hour ambulatory electrocardiography monitoring is an independent risk factor for a poor prognosis in patients with CHF. Whether analysis of HRV could be recommended in the risk stratification for better management of patients with CHF needs further investigation.

Skeletal Muscle Function and Its Relation to Exercise Tolerance in Chronic Heart Failure

OBJECTIVES This study sought to define the relation between muscle function and bulk in chronic heart failure (HF) and to explore the association between muscle function and bulk and exercise capacity. BACKGROUND Skeletal muscle abnormalities have been postulated as determinants of exercise capacity in chronic HF. Previously, muscle function in chronic HF has been evaluated in relatively small numbers of patients and with variable results, with little account being taken of the effects of muscle wasting. METHODS One hundred male patients with chronic HF and 31 healthy male control subjects were studied. They were matched for age (59.0 +/- 1.0 vs. 58.7 +/- 1.7 years [mean +/- SEM]) and body mass index (26.6 +/- 0.4 vs. 26.3 +/- 0.7 kg/m2). We assessed maximal treadmill oxygen consumption (VO2), quadriceps maximal isometric strength, fatigue (20-min protocol, expressed in baseline maximal strength) and computed tomographic cross-sectional area (CSA) at midthigh. RESULTS Peak VO2 was lower in patients (18.0 +/- 0.6 vs. 33.3 +/- 1.4 ml/min per kg, p < 0.0001), although both groups achieved a similar respiratory exchange ratio at peak exercise (1.15 +/- 0.01 vs. 1.19 +/- 0.03, p = 0.13). Quadriceps (582 vs. 652 cm2, p < 0.05) and total leg muscle CSA (1,153 vs. 1,304 cm2, p < 0.005) were lower in patients with chronic HF. Patients were weaker than control subjects (357 +/- 12 vs. 434 +/- 18 N, p < 0.005) and also exhibited greater fatigue at 20 min (79.1% vs. 92.1% of baseline value, p < 0.0001). After correcting strength for quadriceps CSA, significant differences persisted (5.9 +/- 0.2 vs. 7.0 +/- 0.3 N/cm2, p < 0.005), indicating reduced strength per unit muscle. In patients, but not control subjects, muscle CSA significantly correlated with peak absolute VO2 (R = 0.66, p < 0.0001) and is an independent predictor of peak absolute VO2. CONCLUSIONS Patients with chronic HF have reduced quadriceps maximal isometric strength. This weakness occurs as a result of both quantitative and qualitative abnormalities of the muscle. With increasing exercise limitation there is increasing muscle weakness. This progressive weakness occurs predominantly as a result of loss of quadriceps bulk. In patients, this muscular atrophy becomes a major determinant of exercise capacity.

Augmented Peripheral Chemosensitivity as a Potential Input to Baroreflex Impairment and Autonomic Imbalance in Chronic Heart Failure

BACKGROUND The precise mechanisms responsible for the sympathetic overactivity and blunted baroreflex control in chronic heart failure (CHF) remain obscure. Augmented peripheral chemosensitivity has recently been demonstrated in CHF. We evaluated the relation between peripheral chemoreflex sensitivity and autonomic activity in patients with CHF. METHODS AND RESULTS We studied in 26 stable patients with CHF the peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalations of pure nitrogen), autonomic balance (spectral analysis of heart rate variability [HRV]), and baroreflex sensitivity (bolus phenylephrine method and alpha index). To determine whether transient inactivation of peripheral chemoreceptors might influence autonomic balance, 12 patients underwent a second study during which they breathed 100% O2. Peripheral chemosensitivity correlated inversely with HRV power within the low-frequency band (0.04 to 0.15 Hz) (r=-.52, P=.006) and inversely with baroreflex sensitivity (r=-.60, P=.005). When the patients were divided into two groups according to the chemosensitivity of age-matched normal controls (above and below mean+2 SDs of chemosensitivity of control subjects), those above the normal range revealed more impaired autonomic balance, ie, lower baroreflex sensitivity (1.4 +/- 1.3 versus 5.0 +/- 1.5 ms/mm Hg, P<.0001) and depressed values of low-frequency power (2.5 +/- 1.8 versus 4.1 +/- 0.8 ln ms2, P<.005) compared with those with normal chemosensitivity. Transient hyperoxia did not alter heart rate or systolic pressure but resulted in an increase in HRV and an improvement in baroreflex sensitivity. CONCLUSIONS A link between increased peripheral chemosensitivity and impaired autonomic control, including baroreflex inhibition, is demonstrated. The clinical importance of this phenomenon warrants further investigation.

Effects of Dihydrocodeine on Chemosensitivity and Exercise Tolerance in Patients With Chronic Heart Failure

OBJECTIVES We sought to test the hypothesis that suppression of chemosensitivity (respiratory response to arterial blood gases) with dihydrocodeine may improve dyspnea and exercise tolerance in patients with chronic heart failure. BACKGROUND Exertional dyspnea is a common limiting symptom in patients with chronic heart failure. The mechanisms underlying this symptom are not fully understood but may be related to increased ventilation caused, in part, by the augmentation of chemosensitivity. Suppression of chemosensitivity with mild opiates may thus improve this symptom as well as exercise tolerance. METHODS Twelve men with chronic heart failure (mean [+/-SE] age 65.5 +/- 1.5 years, range 58 to 75; left ventricular ejection fraction 21.3 +/- 3.0%, range 8 to 39) received placebo or dihydrocodeine (1 mg/kg body weight) on two separate days in a randomized, double-blind design. One hour later, hypoxic and hypercapnic chemosensitivities were assessed using the transient inhalations of pure nitrogen and the rebreathing of 7% carbon dioxide in 93% oxygen, followed by treadmill cardiopulmonary exercise testing. The symptoms of dyspnea and fatigue during the exercise test were assessed using a modified Borg scale from 0 to 10. RESULTS There was a significant fall in hypoxic and hypercapnic chemosensitivities with dihydrocodeine administration compared with placebo (0.447 +/- 0.096 vs. 0.746 +/- 0.104 liter/min per percent arterial oxygen saturation, p = 0.005; 2,480 +/- 0.234 vs. 2.966 +/- 0.283 liter/min per mm Hg, p = 0.01, respectively). Exercise duration was prolonged from 455 +/- 27 s on placebo to 512 +/- 27 s (p = 0.001) with dihydrocodeine, and peak oxygen consumption increased from 18.0 +/- 0.6 to 19.7 +/- 0.6 ml/kg per min (p = 0.002). The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to carbon dioxide output, decreased from 34.19 +/- 2.35 to 30.85 +/- 1.91 (p = 0.01). With dihydrocodeine administration, the change in the modified Borg score for dyspnea was -0.80 (p = 0.003) at 6 min and -0.33 (p = 0.52) at peak exercise, whereas that for fatigue did not change significantly. Arterial oxygen saturation was maintained during exercise despite dihydrocodeine administration (99.3% at rest vs. 98.9% at peak exercise, p = 0.21). CONCLUSIONS Augmented chemosensitivity is important in the pathophysiology of chronic heart failure. Its suppression with dihydrocodeine was associated with a reduction of exercise ventilation, an improvement in exercise tolerance and a decrease in breathlessness. Pharmacologic modulation of chemosensitivity may benefit patients with chronic heart failure and merits further investigation.

Detection and significance of a discrete very low frequency rhythm in RR interval variability in chronic congestive heart failure

Although in advanced chronic congestive heart failure (CHF) very low frequency (< 0.04 Hz, VLF) oscillations are prominent, the clinical importance and the physiologic basis of these rhythms have not been elucidated. To investigate the physiologic determinants of the VLF rhythms in RR interval variability, we studied 36 patients with stable, moderate to severe CHF (33 men, age: 58 +/- 8 years, ejection fraction 25 +/- 10%, peak oxygen consumption 18.1 +/- 4.6 ml/kg/min) and 12 age- and sex-matched controls using autoregressive spectral analysis of RR interval, blood pressure, and respiratory signals during controlled conditions. We quantified low frequency (LF) (0.04 to 0.15 Hz), high frequency (HF) (0.15 to 0.40 Hz), VLF, and total power (0 to 0.5 Hz), and calculated the coherence between systolic blood pressure and RR interval variability within each band. Peripheral chemosensitivity was assessed by the ventilatory response to hypoxia using transient inhalation of pure nitrogen. The influence of transient inactivation of peripheral chemoreceptors on the VLF rhythm was investigated by exposing 6 patients to hyperoxic (60% oxygen) conditions for 20 minutes. Twenty-three patients (64%) with CHF, but no controls, had a discrete VLF rhythm (0.019 +/- 0.008 Hz) in RR variability. The presence of VLF rhythm was not related to any difference in clinical parameters (etiology, New York Heart Association class, ejection fraction, oxygen uptake) but rather to a different pattern in RR interval and blood pressure variability: lower LF power (2.8 +/- 1.6 ms2 natural logarithm [ln]) compared either to patients without VLF (4.0 +/- 1.3 ms2 ln) or to controls (5.9 +/- 0.7 ms2 ln), higher percentage of power within VLF band (86.3 +/- 8.3% vs 77.5 +/- 7.9% and 61.5 +/- 14.1%) and a markedly impaired coherence between RR interval and systolic blood pressure variability within the LF band (0.26 +/- 0.10 vs 0.42 +/- 0.18 and 0.63 +/- 0.15, in patients with vs without VLF peak and controls, respectively). Patients with VLF had significantly increased hypoxic chemosensitivity, and hyperoxic conditions were able to decrease VLF power and abolish the VLF rhythm in 5 of 6 patients with CHF. Discrete VLF oscillations in RR variability are common in patients with advanced CHF and appear to be related to severely impaired autonomic regulation and suppression of baroreceptor function, with enhancement of hypoxic chemosensitivity. We hypothesize that this rhythm represents an enhanced chemoreflex harmonic oscillation in CHF patients, which may have application for arrhythmogenesis.

The effect of salbutamol on skeletal muscle in chronic heart failure.

We performed a randomised placebo-controlled trial to investigate the effects of the anabolic drug salbutamol on skeletal muscle and exercise capacity in chronic heart failure. Twelve patients received salbutamol slow-release 8 mg twice daily or placebo for 3 weeks. We assessed the effect of treatment on exercise capacity, quadriceps muscle bulk, maximal isometric strength and fatigue, respiratory muscle strength, spirometry and 24-h ECG (electrocardiogram). There was no significant change in the muscle indices, exercise time or peak oxygen consumption. The frequency of ventricular arrhythmias and spirometric measurements were also unchanged. Maximal expiratory mouth pressure, measured at total lung capacity and functional residual capacity, increased significantly (+29.7+/-10.6 vs. -0. 5+/-7.5 cm H(2)O [mean+/-S.E.M., change over 3 weeks treatment salbutamol vs. placebo] and +31.2+/-5.4 vs. +0.2+/-4.0 cm H(2)O both P<0.05). Maximal inspiratory pressures showed a trend towards increasing with treatment when measured from either lung volume (-22. 8+/-9.5 vs. -6.2+/-3.6 cm H(2)O, P=0.14 and -21.5+/-7.5 vs. -3.5+/-3. 4 cm H(2)O, P=0.054). Treatment with 3 weeks of salbutamol increases respiratory muscle strength in chronic heart failure but does not improve quadriceps abnormalities or exercise capacity. Salbutamol is unlikely to have a role in treating the muscle abnormalities in chronic heart failure.

Effect of reduced muscle bulk on the ventilatory response to exercise in chronic congestive heart failure secondary to idiopathic dilated and ischemic cardiomyopathy

Changing the exercising muscle group alters the ventilatory response to exercise in chronic heart failure. The recognized muscle abnormalities in congestive heart failure may thus contribute to the ventilatory abnormalities of this condition.

Effects of Chronic Hypoxemia on Chemosensitivity in Patients With Univentricular Heart

OBJECTIVES We sought to compare the arterial blood gas chemosensitivity in relation to exercise ventilatory response in patients with univentricular heart and cyanosis and in patients with univentricular heart and Fontan-type circulation without cyanosis. BACKGROUND Patients with univentricular heart demonstrate excessive ventilation during exercise. Chronic hypoxemia may alter chemoreceptor function, affecting ventilation. METHODS Cardiopulmonary exercise testing was performed in 10 patients with rest or stress-induced cyanosis (cyanotic group: mean age +/- SE 30.5 +/- 2.3 years; 5 men), 8 patients without cyanosis with Fontan-type circulation (Fontan group: mean age 29.4 +/- 1.5 years; 4 men) and 10 healthy control subjects (normal group: mean age 30.7 +/- 1.9 years; 5 men). Hypoxic and hypercapnic chemosensitivity were assessed by using transient inhalations of pure nitrogen and the rebreathing of 7% CO2 in 93% O2, respectively. RESULTS Peak O2 consumption was comparable in both patient groups (21.7 +/- 2.5 [cyanotic group] vs. 21.0 +/- 1.9 ml/kg per min [Fontan group]) but was lower than that in the normal group (34.7 +/- 1.9 ml/kg per min). The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to CO2 output, was higher in the cyanotic group (43.4 +/- 4.0) than in the Fontan group (31.4 +/- 3.0, p = 0.02) and the normal group (23.1 +/- 1.1). Hypoxic chemosensitivity was blunted in the cyanotic group compared with that in the Fontan and normal groups (0.148 vs. 0.448 [p = 0.02] vs. 0.311 liter/min per percent arterial O2 saturation, respectively) and did not correlate with the ventilatory response to exercise (r = -0.36, p = 0.29). In contrast, hypercapnic chemosensitivity represented by the slope of the hypercapnic-ventilatory response line was similar in the cyanotic, Fontan and normal groups (1.71 vs. 1.76 vs. 1.70 liter/min per mm Hg, respectively), but the response line had shifted to the left in the cyanotic group (x intercept = 31.9 vs. 39.9 mm Hg [p = 0.026]), compared with 45.2 mm Hg in normal subjects. These findings suggest that in the cyanotic group, ventilation is greater for a given level of arterial CO2 tension and thus may partly explain the increased exercise ventilatory response in this group. CONCLUSIONS Hypoxic chemosensitivity is blunted in patients with univentricular heart and cyanosis and does not determine the exercise ventilatory response. CO2 elimination appears more important. The blunting of hypoxic chemosensitivity is reversible once chronic hypoxemia is relieved, as evident in the Fontan group.