Background Chronic heart failure is associated with hyperuricaemia and elevations in circulating markers of inflammation. Activation of xanthine oxidase, through free radical release, causes ...leukocyte and endothelial cell activation. Associations could therefore be expected between serum uric acid level, as a marker of increased xanthine oxidase activity, and markers of inflammation. We have explored these associations in patients with chronic heart failure, taking into account the hyperuricaemic effects of diuretic therapy and insulin resistance. Methods and Results Circulating uric acid and markers of inflammation were measured in 39 male patients with chronic heart failure and 16 healthy controls. All patients underwent a metabolic assessment, which provided a measure of insulin sensitivity (intravenous glucose tolerance tests and minimal modelling analysis). Compared to controls, patients with chronic heart failure had significantly higher levels of circulating uric acid, interleukin-6, soluble tumour necrosis factor receptor (sTNFR)-1, soluble intercellular adhesion molecule-1 (ICAM-1, allP<0·001), E-selectin and sTNFR2 (bothP<0·05). In patients with chronic heart failure, serum uric acid concentrations correlated with circulating levels of sTNFR1 (r=0·74), interleukin-6 (r=0·66), sTNFR2 (r=0·63), TNFα(r=0·60) (allP<0·001), and ICAM-1 (r=0·41,P<0·01). In stepwise regression analyses, serum uric acid emerged as the strongest predictor of ICAM-1, interleukin-6, TNF, sTNFR1 and sTNFR2, independent of diuretic dose, age, body mass index, alcohol intake, serum creatinine, plasma insulin and glucose, and insulin sensitivity. Conclusions Serum uric acid is strongly related to circulating markers of inflammation in patients with chronic heart failure. This is consistent with a role for increased xanthine oxidase activity in the inflammatory response in patients with chronic heart failure.
Peripheral chemoreceptor hypersensitivity is a feature of abnormal cardiorespiratory reflex control in chronic heart failure (CHF) and may contribute to sympathetic overactivity, attenuated ...baroreflex sensitivity (BRS), and excessive ventilation during exercise. We studied whether augmented peripheral chemosensitivity carries independent prognostic significance.
We assessed peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalation of pure nitrogen) and BRS (phenylephrine and spectral methods) in 80 consecutive CHF patients (age 58+/-9 years; left ventricular ejection fraction LVEF 24+/-12%; peak oxygen consumption peak VO(2) 18+/-7 mL(-1). min(-1)). CHF patients demonstrated augmented peripheral chemosensitivity and decreased BRS (all P<0.01 versus reference values). During follow-up (median 41 months, >3 years in all survivors), 37 patients died. High peripheral chemosensitivity (>0.72 L. min(-1). %SaO(2)(-1)) predicted impaired survival (hazard ratio 3.2, 95% CI 1.6 to 6.0, P=0.0006). In the 27 patients (34%) with high peripheral chemosensitivity, 3-year survival was 41% (95% CI 22% to 60%) compared with 77% (66% to 89%) in 53 patients with normal chemosensitivity (P=0.0002). In multivariate analyses, augmented chemosensitivity independently predicted death (hazard ratio 2.8, 95% CI 1.5 to 5.5, adjusted for age, peak VO(2), and VE/VCO(2) P=0.002; hazard ratio 2.6, 95% CI 1.3 to 5.1, adjusted for age, LVEF, and peak VO(2) P=0.008). Depressed BRS was related to unfavorable prognosis in univariate analysis (P=0.05) but not in multivariate analyses.
Hypersensitivity of the peripheral chemoreceptors independently predicts adverse prognosis in ambulatory patients with CHF. This hyperactive excitatory reflex, through its inhibitory effect on the baroreflex, may be the reason for the previously observed prognostic association of the latter.
Heart failure is a major public-health concern. Quality and duration of life on maximum medical therapy are poor. The availability of donor hearts is severely limited, therefore an alternative ...approach is necessary. We have explored the use of a new type of left-ventricular assist device intended as a long-term solution to end-stage heart failure.
As part of a prospective clinical trial, we implanted the first permanent Jarvik 2000 Heart—an intraventricular device with an innovative power delivery system—into a 61-year-old man (New York Heart Association functional class IV) with dilated cardiomyopathy. We assessed the effect of this left-ventricular assist device on both native heart function and the symptoms and systemic characteristics of heart failure.
The Jarvik 2000 Heart sustained the patient's circulation, and was practical and user-friendly. After 6 weeks, exercise tolerance, myocardial function, and end-organ function improved. Symptoms of heart failure have resolved, and continuous decreased pulse-pressure perfusion has had no adverse effects in the short term. There has been no significant haemolysis and no device-related complications. The skull-mounted pedestal is unobtrusive and has healed well.
The initial success of this procedure raises the possibility of a new treatment for end-stage heart failure. In the longer term, its role will be determined by mechanical reliability.
Aims To describe the clinical course of heart failure in a population-based sample of incident cases, and to identify factors predicting hospitalization and mortality. Methods and Results Three ...hundred and thirty-two incident cases were identified over 15 months; 208 inpatients and 124 outpatients. Thirty-eight inpatients died during the first hospital admission (case fatality 18%) leaving 294 at risk of subsequent hospitalization. Over an average follow-up of 19 months, 173 cases were hospitalized on 311 occasions. Two hundred and twenty-four (72%) of these admissions were unplanned, with 51% due to worsening heart failure. One hundred and ten cases died over the same period. Cases diagnosed as an inpatient had 26 more admissions for worsening heart failure per 100 cases during follow-up (95%CI 9 to 44) compared to cases diagnosed as an outpatient, and also a higher mortality (hazard ratio 3·1 (95%CI 1·9 to 5·1)). Age was the only factor associated with an increased risk of hospitalization for worsening heart failure, but age, functional class and serum creatinine were predictive of mortality. Conclusions New cases of heart failure are at high risk of subsequent hospitalization, especially during the first months after diagnosis. Whilst predicting which patients will be hospitalized is difficult, interventions designed to reduce hospitalizations for worsening heart failure should be targeted at elderly inpatients with a new diagnosis. Copyright 2001 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved
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.
Objective: To investigate markers that predict modes of death in patients with chronic heart failure. Design: Randomised, double blind, three period, comparative, parallel group study (ATLAS, ...assessment of treatment with lisinopril and survival). Patients: 3164 patients with mild, moderate, or severe chronic heart failure (New York Heart Association functional class II–IV). Interventions: High dose (32.5 or 35 mg) or low dose (2.5 or 5 mg) lisinopril once daily for a median of 46 months. Main outcome measures: All cause mortality, cardiovascular mortality, sudden death, and chronic heart failure death related to prognostic factors using competing risks analysis. Mode of death was classified by trialists and by an independent end point committee. Results: Age, male sex, pre-existing ischaemic heart disease, increasing heart rate, creatinine concentration, and certain drugs taken at randomisation were markers of increased risk of all cause mortality and cardiovascular death. There were risk markers for sudden death that were different from the risk markers for death from chronic heart failure. Low systolic blood pressure at baseline, raised creatinine, reduced serum sodium or haemoglobin, and increased heart rate were associated with chronic heart failure death. Use of β blockers or antiarrhythmic agents (mainly amiodarone) was associated with a reduced risk of sudden death, whereas long acting nitrates and previous use of angiotensin converting enzyme inhibitors were markers for increased risk. Conclusions: The use of competing risks analysis on the data from the ATLAS study has identified variables associated with certain modes of death in heart failure patients. This approach to analysing outcomes may make it possible to predict which patients might benefit most from particular therapeutic interventions.
Abstract Central sleep apnoea (CSA) occurs in up to 40% of patients with chronic heart failure (CHF). It is thought to be a consequence of CHF and is associated with an accelerated decline in cardiac ...function, and increased morbidity and mortality. The optimal treatment of CSA remains unclear. Resolution of CSA has been reported after cardiac transplantation. We report the first case of resolution of CSA 10 months following implantation of a permanent Jarvik™ 2000 left ventricular assist device (LVAD). The correction of CSA after implantation of the LVAD was associated with improvements in symptoms, exercise capacity, renal function, and increased arterial carbon dioxide levels at rest during wakefulness and also reduction in brain natriuretic peptide.
Heart failure has an annual mortality rate ranging from 5% to 75%. The purpose of the study was to develop and validate a multivariate risk model to predict 1-, 2-, and 3-year survival in heart ...failure patients with the use of easily obtainable characteristics relating to clinical status, therapy (pharmacological as well as devices), and laboratory parameters.
The Seattle Heart Failure Model was derived in a cohort of 1125 heart failure patients with the use of a multivariate Cox model. For medications and devices not available in the derivation database, hazard ratios were estimated from published literature. The model was prospectively validated in 5 additional cohorts totaling 9942 heart failure patients and 17,307 person-years of follow-up. The accuracy of the model was excellent, with predicted versus actual 1-year survival rates of 73.4% versus 74.3% in the derivation cohort and 90.5% versus 88.5%, 86.5% versus 86.5%, 83.8% versus 83.3%, 90.9% versus 91.0%, and 89.6% versus 86.7% in the 5 validation cohorts. For the lowest score, the 2-year survival was 92.8% compared with 88.7%, 77.8%, 58.1%, 29.5%, and 10.8% for scores of 0, 1, 2, 3, and 4, respectively. The overall receiver operating characteristic area under the curve was 0.729 (95% CI, 0.714 to 0.744). The model also allowed estimation of the benefit of adding medications or devices to an individual patient's therapeutic regimen.
The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival with the use of easily obtained clinical, pharmacological, device, and laboratory characteristics.
Aims An analysis was designed to determine whether chronic heart failure patients at high cardiovascular risk benefited to the same extent from high-dose lisinopril as the whole ATLAS population. ...Methods and Results A retrospective analysis was performed on high-risk heart failure patients in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial (total number of patients 3164) comparing highdose (32·5–35mg.day−1) vs low-dose (2·5–5mg.day−1) lisinopril for a median of 46 months. These high-risk patients included those with hypotension, hyponatraemia, compromised renal function, the elderly and patients with diabetes mellitus at baseline. In the whole study population, high-dose lisinopril led to a trend in risk reduction of all-cause mortality (primary end-point P=0·128) and a significant risk reduction in all-cause mortality plus hospitalization (principal secondary end-point P=0·002). Subgroup analyses were performed for these end-points. There were no consistent interactions between age, baseline sodium, creatinine or potassium values, and treatment effect. Diabetics showed a beneficial response to high-dose therapy that was at least as good as that in non-diabetics. The underlying higher morbidity/mortality rates in diabetics mean that high-dose lisinopril has potential for a larger absolute clinical impact in these patients. Conclusion Long-term high-dose lisinopril was as effective and well-tolerated in high-risk patients, including those with diabetes mellitus, as for the ATLAS study population as a whole.
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