The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure.
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).
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.
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 (V̇e–V̇co2slope) 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; V̇e–V̇co2slope 34.8 ± 10.6) over a 2-year period. Using 1.96 standard deviations above the mean V̇e–V̇co2slope 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 V̇e–V̇co2slope (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 V̇e–V̇co2slope was an important prognostic factor (p < 0.0001). In the multivariate Cox analyses using several variables (age, peak oxygen consumption, V̇e–V̇co2slope and LVEF), the V̇e–V̇co2slope 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 V̇e–V̇co2slope compared with 69% in those with a high slope (p < 0.0001).
Conclusions. A high V̇e–V̇co2slope selects patients with more severe heart failure and is an independent prognostic marker. The V̇e–V̇co2slope may be used as a supplementary index in the assessment of patients with chronic heart failure.
(J Am Coll Cardiol 1997;29:1585–90)
A molecular map has been constructed for the rice genome comprised of 726 markers (mainly restriction fragment length polymorphisms; RFLPs). The mapping population was derived from a backcross ...between cultivated rice, Oryza sativa, and its wild African relative, Oryza longistaminata. The very high level of polymorphism between these species, combined with the use of polymerase chain reaction-amplified cDNA libraries, contributed to mapping efficiency. A subset of the probes used in this study was previously used to construct an RFLP map derived from an inter subspecific cross, providing a basis for comparison of the two maps and of the relative mapping efficiencies in the two crosses. In addition to the previously described PstI genomic rice library, three cDNA libraries from rice (Oryza), oat (Avena) and barley (Hordeum) were used in this mapping project. Levels of polymorphism detected by each and the frequency of identifying heterologous sequences for use in rice mapping are discussed. Though strong reproductive barriers isolate O. sativa from O. longistaminata, the percentage of markers showing distorted segregation in this backcross population was not significantly different than that observed in an intraspecific F2 population previously used for mapping. The map contains 1491 cM with an average interval size of 4.0 cM on the framework map, and 2.0 cM overall. A total of 238 markers from the previously described PstI genomic rice library, 250 markers from a cDNA library of rice (Oryza), 112 cDNA markers from oat (Avena), and 20 cDNA markers from a barley (Hordeum) library, two genomic clones from maize (Zea), 11 microsatellite markers, three telomere markers, eleven isozymes, 26 cloned genes, six RAPD, and 47 mutant phenotypes were used in this mapping project. Applications of a molecular map for plant improvement are discussed
The presence of
occult bone marrow metastases (OM) has been reported to represent an
important prognostic indicator for patients with operable breast cancer
and other malignancies. Assaying for OM ...most commonly involves
labor-intensive manual microscopic analysis. The present report
examines the performance of a recently developed automated
cellular image analysis system (ACIS; ChromaVision Medical Systems,
Inc.) for identifying and enumerating OM in human breast cancer
specimens. OM analysis was performed after immunocytochemical staining.
Specimens used in this study consisted of normal bone marrow
( n = 10), bone marrow spiked with carcinoma cells
( n = 20), and bone marrow obtained from breast
cancer patients ( n = 39). The reproducibility of
ACIS-assisted analysis for tumor cell detection was examined by having
a pathologist evaluate montage images generated from multiple ACIS runs
of five specimens. Independent ACIS-assisted analysis resulted in the
detection of an identical number of tumor cells for each specimen in
all instrument runs. Additional studies were performed to analyze OM
from 39 breast cancer patients with two pathologists performing
parallel analysis using either manual microscopy or ACIS-assisted
analysis. In 17 of the 39 cases (44%), specimens were classified by
the pathologist as positive for tumor cells after ACIS-assisted
analysis, whereas the same pathologist failed to identify tumor cells
on the same slides after analysis by manual microscopy. These studies
indicate that the ACIS-assisted analysis provides excellent sensitivity
and reproducibility for OM detection, relative to manual microscopy.
Such performance may enable an improved approach for disease staging
and stratifying patients for therapeutic intervention.
Using restriction fragment–length polymorphism data, we conducted a retrospective cohort study of 139 adult patients with pulmonary tuberculosis to investigate the clinical impact of Mycobacterium ...tuberculosis infection with a clustered isolate. The cumulative all-cause mortality rate during treatment was 21%. Patients with clustered DNA fingerprint patterns had a reduced risk of death, compared with patients with unique patterns (hazard ratio HR, 0.5; 95% confidence interval CI, 0.2–1.1), but this finding was confounded by age (adjusted HR, 0.8; 95% CI, 0.4–1.8). After adjustment for age, the strongest predictors of death were such underlying illnesses as diabetes mellitus, renal failure, chronic obstructive pulmonary disease, and human immunodeficiency virus infection. We conclude that comorbidity and immunosuppression are important predictors of survival for patients with pulmonary tuberculosis in an inner-city cohort. Recently transmitted infection, as determined by use of DNA fingerprinting to classify patients' isolates as being either clustered or unique, was not independently associated with death.
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 (V̇o2), quadriceps maximal isometric strength, fatigue (20-min protocol, expressed in baseline maximal strength) and computed tomographic cross-sectional area (CSA) at midthigh.
Results. Peak V̇o2was 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 V̇o2(R = 0.66, p < 0.0001) and is an independent predictor of peak absolute V̇o2.
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.
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). Cox's 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.
In 102 consecutive patients with stable chronic congestive heart failure and sinus rhythm, several heart rate variability measures derived from 24-hour electrocardiographic recording were significant prognostic risk markers, independent of clinical variables (New York Heart Association class, peak oxygen consumption, left ventricular ejection fraction). The coexistence of the standard deviation of all normal RR intervals <100 ms and peak oxygen consumption <14 ml/kg/min had the worst prognosis, and it is concluded that heart rate variability analysis is useful for noninvasive heart transplant assessment.
Although adherence to HAART at a level above 95% has been associated with optimal viral suppression, the impact of different levels of adherence on long-term clinical outcomes has not been ...determined. We used an objective pharmacy-based measure to examine the association between three levels of adherence to HAART and disease progression among a population-based cohort of HIV-infected patients attending an urban HIV specialty clinic. Higher levels of adherence to HAART were significantly associated with longer time to virologic failure (P < 0.001), greater increase in CD4 cell count (P = 0.04), and lower risk of progression to clinical AIDS or death (P < 0.007). After controlling for other factors, patients with low adherence had over five times the risk of disease progression than patients with moderate adherence (P = 0.007) or patients with high adherence (P = 0.001). There was no significant difference in the risk of progression between patients with moderate and high levels of adherence (P > 0.2). Patients who progressed to AIDS or death had significantly higher viral loads (P = 0.01) and lower CD4 cell counts (P = 0.03) than patients who experienced virologic failure, but did not progress.
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.
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.
A link between increased peripheral chemosensitivity and impaired autonomic control, including baroreflex inhibition, is demonstrated. The clinical importance of this phenomenon warrants further investigation.
In guinea‐pig ileum, ageing has been associated with a decrease in enteric neurons. This study examined guinea‐pig colon and measured changes in gut dimensions, neuron size, density and ganglionic ...area. Changes in motor nerve fibres in the circular muscle were also measured. Myenteric neurons in whole‐mount preparations of mid‐colon from 2‐week, 6‐month, and 2‐year‐old guinea‐pigs were labelled immunohistochemically with the neuronal marker human neuronal protein HuC/HuD, and numbers of neurons mm−2, neuronal size, ganglionic area mm−2, gut length, circumference and muscle thickness were measured. Corrected numbers of neurons mm−2 and ganglionic area mm−2 accounting for growth of the colon were calculated. Additionally, nerve fibres in circular muscle cross‐sections were labelled with antibodies against nitric oxide synthase (NOS) and substance P (SP) and the density of nerve fibres in circular muscle was measured. The numbers of neurons mm−2 decreased by 56% (from 2 weeks to 2 years) with no change in neuron size. Total neuron numbers decreased by 19% (P = 0.14) when adjusted for changes in length and circumference with age. The percentage area of NOS‐ and SP‐immunoreactive (IR) nerve fibres in the circular muscle decreased (P < 0.001), but the total area of NOS and SP‐IR nerve fibres increased (P < 0.01) due to an age‐related increase in muscle thickness. The density of myenteric neurons in guinea‐pig mid‐colon halved from 2 weeks to 2 years, but when the increase in colon dimensions was considered, the number of neurons decreased by only 19%. The percentage area of motor nerve fibres in the circular muscle decreased with no change in total volume of nerve fibres.
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