Non-Gaussian heart rate as an independent predictor of mortality in patients with chronic heart failure

BACKGROUND: Morbidity and mortality due to chronic heart failure remain unacceptably high despite effective drug therapies, and the search for a better risk predictor is ongoing. Statistics derived from beat-to-beat fluctuations in heart rate or heart rate variability (HRV) have been used for this purpose, but the current predictability level is low or moderate at best. OBJECTIVE: The purpose of this study was to evaluate whether a recently proposed non-Gaussian index of HRV is a significant and independent mortality predictor in patients with congestive heart failure (CHF). METHODS: Twenty-four-hour Holter ECGs from 108 CHF patients were evaluated. Thirty-nine (36.1%) of the patients died during the follow-up period of 33 +/- 17 months. Cox proportional hazards regression analysis was performed to determine factors related to all-cause mortality. The factors evaluated derived from clinical information, including plasma brain natriuretic peptide, conventional time- and frequency-domain and fractal HRV measures, and a recently proposed non-Gaussian index lambda of HRV. RESULTS: The short-term (<40 beats) non-Gaussian index lambda(40) (hazard ratio per increment of unit standard deviation 1.64, 95% confidence interval [1.23, 2.18], P <.001) and the long-term (<1,000 beats) index lambda(1000) (hazard ratio 1.42, 95% confidence interval [1.07, 2.18], P <.02), together with brain natriuretic peptide (hazard ratio 2.26, 95% confidence interval [1.45, 3.53], P <.001), are significant univariate risk predictors of mortality. In a multivariate model, lambda(40) (1.49, [1.13, 1.96], P <.005) and brain natriuretic peptide (2.39, [1.53, 3.75], P <.001) are independent predictors of the survival statistics of patients. None of the conventional HRV measures have predicted the mortality of patients in a significant and independent manner. CONCLUSION: The results of this study indicate the usefulness of the short-term non-Gaussian index of HRV for risk prediction in patients with CHF.     

Renal insufficiency is an independent predictor of mortality after percutaneous coronary intervention

The present study was designed to evaluate whether the presence of renal disease during percutaneous coronary intervention (PCI) is associated with worse outcomes at 1 year in a multicenter study. The incidence of death, myocardial infarction, coronary artery bypass grafting, repeat PCI, and repeat revascularization were prospectively collected on 4,602 patients (6,542 lesions) in 2 waves of patients who underwent PCI in 17 centers between July 1997 and June 1999. Renal disease was defined as the presence of an increased creatinine level in a patient with a history or presence of renal failure treated with low protein diet or dialysis. Patients with renal disease (n = 192) were older and more likely to have diabetes, heart failure, reduced ejection fraction, known coronary disease, and multivessel disease than patients without renal disease (n = 4,410). Rates of stenting were equivalent (68.2% vs 73.0%, p = NS). Patients with renal disease had lower angiographic success (84.9% vs 92.8%, p <0.001) and higher mortality, both in-hospital (5.7% vs 1.2%, p <0.001) and at 1 year (19.7% vs 4.4%, p <0.0001). After adjusting for clinical, demographic, and angiographic differences, renal disease remained an independent predictor of in-hospital (odds ratio 3.81, 95% confidence interval 1.70 to 8.58) and 1-year (risk ratio 2.46, 95% confidence interval 1.64 to 3.68) mortality. Renal disease conferred additional mortality risk in established high-risk clinical subgroups. In conclusion, after adjusting for a higher frequency of co-morbidities, renal disease remains a strong and independent predictor of increased in-hospital and 1-year mortality after PCI and is additive to other clinical markers of worse outcome.     

Serum adiponectin level as an independent predictor of mortality in patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with altered energy homeostasis and myocardial inflammation, hypertrophy, and fibrosis. Adiponectin, an insulin-sensitizing adipocytokine, may affect these pathogenic factors, and the circulating adiponectin level may serve as a biological marker of CHF. This study aimed to assess the significance of serum adiponectin as a prognostic marker for Japanese CHF patients. METHODS AND RESULTS: The serum adiponectin levels were compared between 54 (24 ischemic and 30 non-ischemic) CHF patients with left ventricular systolic dysfunction and 55 age- and gender-matched control subjects. The CHF patients also underwent simultaneous clinical assessment and measurements for brain natriuretic peptide (BNP) and parameters of lipid or glucose metabolism. Compared with the controls, the CHF patients showed significantly increased serum adiponectin levels [6.7 (4.9-12.6) vs 14.6 (9.7-25.4) microg/ml, p<0.0001]. In the CHF patients, the log-transformed values of the serum adiponectin levels positively correlated with the log-transformed values of the plasma BNP levels (p=0.0003, r=0.48) and inversely correlated with the body mass index (p=0.0006, r=-0.46). Furthermore, an increase in the serum adiponectin level was associated with higher mortality (p<0.05), particularly in the ischemic CHF patients (p<0.005). CONCLUSIONS: An increase in the circulating adiponectin level was associated with higher mortality in the ischemic CHF patients. Adiponectin may be an informative risk marker for Japanese CHF patients.     

Right ventricular dysfunction as an independent predictor of short- and long-term mortality in patients with heart failure

BACKGROUND: The prognostic importance of right ventricular (RV) dysfunction in heart failure (HF) has been suggested in patients with severe systolic heart failure. Tricuspid annular plane systolic excursion (TAPSE) is a simple echocardiographic measure of RV ejection fraction, but may be affected by co-existing chronic obstructive pulmonary disease (COPD). AIMS: To examine the prognostic information from TAPSE adjusted for the potential confounding effects of co-existing cardiovascular and COPD in a large series of patients admitted for new onset or worsening HF. METHODS AND RESULTS: Eight hundred and seventeen patients screened for participation in a large clinical trial by trans-thoracic echocardiography, including measurement of TAPSE, were followed for a median of 4.1 years (maximum 5.5 years). Decreased TAPSE as well as presence of COPD were independently associated with adverse short- and long-term survival, hazard ratio was 0.74 (p=0.004) for every doubling of TAPSE; and 2.4 (p<0.0001) for the presence of COPD. CONCLUSION: Decreased RV systolic function as estimated by TAPSE is associated with increased mortality in patients admitted for HF, and is independent of other risk factors in HF including left ventricular function. The co-existence of COPD is also associated with an adverse prognosis independent of the RV systolic function.     

The pro-apoptotic serum activity is an independent mortality predictor of patients with heart failure.

AIM: Systemic inflammation with elevated serum levels of circulating pro-inflammatory cytokines is a major determinant of prognosis in heart failure (HF). Since serum of patients with HF induces apoptosis of endothelial cells (EC), we aimed to determine whether the pro-apoptotic activity in the serum may predict prognosis of patients with HF. METHODS AND RESULTS: We measured the pro-apoptotic activity in the serum of 48 patients with HF of different aetiology by an ex vivo cell culture assay and subsequently monitored these patients for the single endpoint all-cause mortality. During follow-up, 16 patients died and 11 patients received a heart transplant. Survivors had a lower pro-apoptotic serum activity (P=0.007). By univariate analysis, pro-apoptotic serum activity, NYHA class, pro-BNP, low blood pressure, and creatinine levels were significantly associated with mortality. In a multivariable stepwise Cox-regression model, the pro-apoptotic serum activity (adjusted hazard ratio, HR=1.85 per %, P=0.008), elevated pro-BNP levels (HR=9.35 per log[pro-BNP], P=0.001), and low blood pressure (HR=0.96 per mmHg, P=0.041) remained as independent predictors of death. CONCLUSION: In this exploratory study, the pro-apoptotic serum capacity is independently associated with a worse prognosis in patients with HF, suggesting that the assessment of serum-induced EC apoptosis could provide an integrative estimate of the deleterious effects of various pro-inflammatory cytokines and other cytotoxic factors in HF.     

Tissue inhibitor of metalloproteinases levels in patients with chronic heart failure: an independent predictor of mortality

BACKGROUND: Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in cardiac remodelling. The prognostic utility of TIMP is unknown in chronic heart failure (CHF). AIMS: We investigated the association of plasma levels of soluble MMP-9 and TIMP-1 with clinical, laboratory and echocardiographic parameters and estimated their prognostic value in the prediction of all-cause death. METHODS: MMP-9, TIMP-1, tumour necrosis factor-alpha, and amino-terminal pro-brain natriuretic peptide were measured in 249 consecutively enrolled CHF patients and 74 healthy individuals. RESULTS: After adjustment for age, sex and creatinine, levels of TIMP-1 (1640 vs. 735 ng/ml, P<0.001) but not MMP-9 were elevated in CHF patients compared to controls. During a median follow-up period of 2.5 years, 66 patients (27%) died. In multivariable Cox regression models TIMP-1 but not MMP-9 emerged as an independent predictor of all-cause death (hazard ratio per tertile, 3.5; 95% confidence interval [CI], 2.2-5.1). In addition to the full set of univariately predictive clinical and serological markers, information on TIMP-1 significantly increased the area under the receiver operating characteristic curve from 0.77 (95% CI, 0.71-0.84) to 0.87 (95% CI, 0.82-0.92). CONCLUSION: In stable CHF patients, TIMP-1 but not MMP-9 is of independent and incremental value regarding the prediction of all-cause death.     

Social network as a predictor of hospital readmission and mortality among older patients with heart failure

BackgroundThis study examines the relationship between social network and hospital readmission and mortality in older patients with heart failure.Methods and ResultsProspective study conducted with 371 patients, age 65 and older, admitted for heart failure–related emergencies at 4 Spanish hospitals. Social network was measured at baseline with a 4-item questionnaire that ascertained whether subjects were married, lived with another person(s), saw or had telephone contact with family members daily or almost daily, and were at home alone for less than 2 hours per day. Social network was deemed “high” where all 4 items were present, “moderate” where 3 were present, and “low” where 2 or fewer were present. Analyses were performed using Cox models, and adjusted for the main confounders. A total of 55% of patients had high or moderate social networks. During a median follow-up of 6.5 months, 135 (36.4%) patients underwent a first emergency rehospitalization and 68 (18.3%) died. Compared with patients with high social network, hospital readmission was more frequent among those who had moderate (hazard ratio [HR] 1.87; 95% confidence interval [CI] 1.06–3.29; P < .05) and low social networks (HR 1.98; 95% CI 1.07–3.68; P < .05). This relationship showed a positive dose-response (p for linear trend 0.042). The magnitude of this association was comparable to that of other important predictors of readmission, such as previous hospitalization. No relationship was observed between social network and death.ConclusionA very simple questionnaire measuring social network can identify patients with a higher short-term risk of hospital readmission.     

Decreased renal function as an independent predictor of re-hospitalization for congestive heart failure.

BACKGROUND: Patients with congestive heart failure (CHF) are often re-hospitalized, worsening both their quality of life and prognosis. Although renal dysfunction reportedly increases the risk of CHF, the association between renal dysfunction and re-hospitalization for CHF remains unclear. METHODS AND RESULTS: Patients with CHF and decreased renal function were reviewed. The estimated glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients with decreased renal function (estimated GFR on admission <45 ml .min(-1) . 1.73 m(-2)) were re-hospitalized more frequently than were patients with preserved renal function (estimated GFR on admission >or=45). Patients with decreased renal function were older and had higher rates of anemia, worsening renal function during hospitalization, and previous hospitalization for CHF. Independent predictors of re-hospitalization for CHF identified with multivariate analysis were age, previous hospitalization for CHF, decreased renal function, and non-use of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. CONCLUSIONS: Renal dysfunction is an independent predictor of re-hospitalization for CHF, so careful follow-up is needed, even after discharge.     

Plasma brain natriuretic peptide--an independent predictor of cardiovascular mortality in acute heart failure

PURPOSE: To examine the prognostic importance of both plasma atrial natriuretic and B-(brain natriuretic peptide) following an episode of acute heart failure. SUBJECTS AND METHODS: A prospective cohort of 91 patients admitted into hospital with acute heart failure were recruited. After initial in-hospital management plasma ANP and BNP levels were measured by radioimmunoassay, and echocardiography was performed on the same day. Patients were followed up for 12 months and the main outcome measure was cardiovascular death. RESULTS: Plasma ANP and BNP levels were significantly higher in patients who died of a cardiovascular cause within 12 months (P<0.001 and P<0.0001, respectively) or at 1-month (P<0.05 and P<0.001) after recruitment. By Kaplan-Meier estimated life-table curves, patients with above median plasma ANP or BNP levels had significantly higher 1-year mortality (42.5% vs. 11.6%, both P<0.005). By multivariate Cox proportional hazard regression analysis, the plasma BNP level was the most important prognostic factor predicting mortality (chi2 = 18.3, P<0.0001), followed by age (chi2 = 11.5, P<0.001). Other factors including ANP, left ventricular ejection fraction by M-mode echocardiography, pulmonary arterial pressure, sex, cause of heart failure as well as New York Heart Association class were not significant. CONCLUSION: A plasma BNP level has independent and at least short-term prognostic significance in patients admitted with acute heart failure. This non-invasive and readily available blood test should be considered for risk stratification in patients with acute heart failure.     

Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals

OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events. BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear. METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women. RESULTS: An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine. CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.     

Renal function as a predictor of prognosis in chronic heart failure

The incidence of chronic heart failure (CHF) has been increasing, particularly because of the aging of the population and the improved survival of patients with coronary artery disease. Therefore, the current pathophysiological and clinical considerations in the diagnosis and treatment of CHF will need further improvement in terms of cardiovascular risk profiling, preventive measures, earlier intervention, and patient-tailored disease management. To date, the role of the kidney in CHF is mainly considered within the context of excessive salt and water retention, due to reduced renal blood flow. However, recent data indicate that the kidney may play a more decisive role in the progression and prognosis of the disease. It has been demonstrated that renal function is independently associated with an increased risk for all-cause mortality and cardiovascular morbidity. Furthermore, moderate renal insufficiency is a common phenomenon in this patient population and, for example, left ventricular ejection fraction, glomerular filtration rate, and New York Health Association class are not only prognostically important but are also acting independently, and support the hypothesis that cardiac function, clinical status, and renal function represent, in part, different prognostic entities of CHF. It could be questioned why an impaired renal function adds prognostic risk to develop CHF? A subclinically decreased renal function is unlikely to be the direct cause. Renal function is known to correlate with a variety of cardiovascular risk factors. Similar risk factors could contribute to the pathogenesis of intrarenal disease. Furthermore, a large number of metabolic abnormalities are related to impaired renal function and induce myocardial dysfunction and damage. Finally, neurohormonal activation is apparent in patients with chronic heart failure. Angiotensin II, the central product of the renin-angiotensin system, may play a central role in the pathophysiology and progression of cardiovascular and renal diseases. In conclusion, to prevent cardiovascular morbidity and mortality, new therapeutic strategies might be triggered by focussing on increasing our knowledge concerning adaptive and maladaptive mechanisms of the kidney involved in CHF.     

Lipopolysaccharide responsiveness is an independent predictor of death in patients with chronic heart failure

BackgroundThe origin of pro-inflammatory activation in chronic heart failure (HF) remains a matter of debate. Lipopolysaccharide (LPS) may enter the blood stream through the morphologically altered and leaky gut barrier. We hypothesized that lower LPS reactivity would be associated with worse survival as compared to normal or higher LPS reactivity.MethodsLPS responsiveness was studied in 122 patients with chronic HF (mean ± SD: age 67.3 ± 10.3 years, 24 female, New York Heart Association class [NYHA] class: 2.5 ± 0.8, left ventricular ejection fraction [LVEF]: 33.5 ± 12.5%) and 27 control subjects of similar age (63.7 ± 7.7 years, p > 0.05). Reference LPS was added at increasing doses to ex vivo whole blood samples and necrosis factor-α (TNFα) was measured. Patients were subgrouped into good- and poor-responder status according to their potential to react to increasing doses of LPS (delta TNFα secretion). The optimal cut-off value was calculated by receiver–operator characteristic curve (ROC) analysis.ResultsA total of 56 patients with chronic HF died from any cause during follow-up. At 24 months, cumulative mortality was 16.4% (95% confidence interval 16.0–16.7%). The delta TNFα value representing the optimal cut-off for the prediction of mortality was 1522 pg/mL (24 months) with a sensitivity of 49.3% (95% confidence interval 37.2–61.4%) and specificity of 81.5% (95% confidence interval 61.9–93.6%). LPS responder status remained an independent predictor of death after multivariable adjustment (hazard ratio 0.09 for good- vs. poor-responders, 95% confidence interval 0.01–0.67, p < 0.05).ConclusionsLPS responsiveness in patients with chronic HF is an independent predictor of death.     

Anaemia is an independent predictor of poor outcome in patients with chronic heart failure

Background: Mild anaemia frequently occurs in patients with chronic heart failure (CHF), particularly in the advanced stages of the disease. The correction of anaemia with erythropoietin is a therapeutic possibility. The aim of this study was to assess prospectively the relationship between the prevalence of anaemia (haemoglobin level≤120 g/l) and prognosis in an unselected CHF population. Methods: All consecutive patients with a diagnosis of CHF admitted to our department between January 2000 and April 2000 were considered for the present study. Those with secondary causes of anaemia were excluded. Patients were followed up until November 2001 (>18 months in all survivors), and the end-point of the study was all-cause mortality. Results: A total of 176 patients were enrolled (mean age: 63 years, New York Heart Association (NYHA) classification I/II/III/IV: 15/81/51/29; left ventricular ejection fraction (LVEF): 42%, ischaemic aetiology in 62%). In the whole population the mean haemoglobin level was 140±15 g/l. Anaemia was found in 18 (10%) patients, and was significantly more common in women than in men (18 vs. 7%, respectively, P=0.02) and in those with most severe CHF symptoms (frequency in NYHA I/II/III/IV: 0/9/10/21%, respectively; NYHA IV vs. I–III, P=0.03), but not related to the other clinical indices. Univariate analysis revealed NYHA class III–IV (hazard ratio 3.8, 95% CI: 1.6–8.9, P=0.003), low LVEF <35% (hazard ratio 2.3, 95% CI: 1.0–4.9, P=0.04) and anaemia (hazard ratio 2.9, 95% CI: 1.2–7.2, P=0.02) as predictors of 18-month mortality. In multivariate analysis, anaemia remained an independent predictor of death when adjusted for NYHA class and LVEF (hazard ratio: 2.6, 95% CI: 1.0–6.5, P=0.04). In anaemic patients, 18-month survival was 67% (95% CI: 45–89%) compared to 87% (81–92%) in patients with a normal haemoglobin level (P=0.016). Conclusions: Mild anaemia is a significant and independent predictor of poor outcome in unselected patients with CHF. Correction of low haemoglobin level may become an interesting therapeutic option for CHF patients.     

Retinopathy as an independent predictor of all-cause mortality in individuals with type 2 diabetes

AimsTo assess whether the presence and grade of diabetic retinopathy (DR) predict all-cause mortality, independent of risk factors for cardiovascular disease (CVD) and other complications, including diabetes-related kidney disease (DKD) and CVD, in individuals with type 2 diabetes mellitus.MethodsProspective cohort study that enroled 15,773 patients in 19 Italian centers in 2006–2008. DR ascertained by fundoscopy, DKD by albuminuria and estimated glomerular filtration rate, and prior CVD by hospital discharge records. All-cause mortality retrieved for 15,656 patients on 31 October 2015.ResultsThe adjusted risk of death was increased in patients with any DR (hazard ratio, 1.136 [95% confidence interval, 1.054;1.224] P < 0.0001), advanced DR, including severe non-proliferative and proliferative DR and diabetic macula edema (1.213 [1.097;1.340] P < 0.0001), and especially proliferative DR alone (1.381 [1.207;1.580] P < 0.0001), compared with those without DR. The impact of DR was more evident in patients without than in those with DKD or CVD. Mortality risk was increased in participants with DR alone, though much less than in those with DKD or CVD alone and particularly in those with both DR and DKD or CVD. DR grade was related to mortality in individuals without DKD or CVD, whereas it conferred no additional risk to those with albuminuric or nonalbuminuric DKD or established CVD.ConclusionsIn patients with type 2 diabetes mellitus, the excess mortality risk conferred by DR is relatively small and higher in those without DKD and CVD, suggesting that it may be mediated by the concurrent presence of these complications, even at a subclinical level.