Chronobiology of death in heart failure.

INTRODUCTION AND OBJECTIVES: In the general population, heart events occur more often during early morning, on Mondays, and during winter. However, the chronobiology of death in heart failure has not been analyzed. The aim of this study was to determine the circadian, day of the week, and seasonal variability of all-cause mortality in chronic heart failure. METHODS: This was an analysis of all consecutive heart failure patients followed in a heart failure unit from January 2003 to December 2008. The circadian moment of death was analyzed at 6-h intervals and was determined by reviewing medical records and by information provided by the relatives. RESULTS: Of 1196 patients (mean [standard deviation] age, 69 [13] years; 62% male), 418 (34.9%) died during a mean (standard deviation) follow-up of 29 (21) months. Survivors were younger, had higher body mass index, left ventricular ejection fraction, glomerular filtration rate, hemoglobin and sodium levels, and lower Framingham risk scores, amino-terminal pro-B type natriuretic peptide, troponin T, and urate values. They were more frequently treated with angiotensin receptor blockers, beta-blockers, mineralocorticoids receptor antagonists, digoxin, nitrates, hydralazine, statins, loop diuretics, and thiazides. The analysis of the circadian and weekly variability did not reveal significant differences between the four 6-h intervals or the days of the week. Mortality occurred more frequently during the winter (30.6%) compared with the other seasons (P = .024). CONCLUSIONS: All cause mortality does not follow a circadian pattern, but a seasonal rhythm in patients with heart failure. This finding is in contrast to the circadian rhythmicity of cardiovascular events reported in the general population.

New insights into lipid raft function regulating myocardial vascularization competency in human idiopathic dilated cardiomyopathy.

OBJECTIVE: Idiopathic dilated cardiomyopathy (IDCM) affects myocardial vascularization. Whether a lack of demand for increased myocardial vascularization and/or an impaired response of circulating angiogenic-supportive cells are responsible for the vascular derangements found in IDCM is unknown. METHODS AND RESULTS: Left ventricle (LV) samples obtained at transplant from IDCM hearts were compared to control hearts from non-cardiac decedents. Peripheral colony-forming myeloid cells were extracted from age- and sex-matched IDCM patients and healthy volunteers. At the tissue level, no differences were detected in stromal cell-derived factor (SDF)-1α expression, but integrin-linked kinase (ILK) levels and activity were increased in IDCM. A marked co-localization of SDF-1α and the specific marker of cholesterol-enriched lipid rafts Flotillin (Flot)-1 was found in IDCM. SDF-1α was also highly distributed into IDCM lipid rafts. Non-adherent pro-angiogenic cells from both groups, which were found increased in patients but showed similar surface levels of CXCR-4, equally supported Matrigel-mediated cell network formation. However, SDF-1-mediated migration was reduced in IDCM-derived cells, which also exhibited decreased ILK activity and downstream ERK activation. CONCLUSIONS: Taken together, our results point out that myocardial competency to increase vascularization is not altered in IDCM, but dysfunctional SDF-1-mediated migration by peripheral pro-angiogenic cells through ILK and downstream ERK signaling may compromise endothelial recovery in patients. We provide new insights into lipid raft function in human IDCM and envision more effective treatments.

Usefulness of body mass index to characterize nutritional status in patients with heart failure.

The obesity paradox in heart failure (HF) is criticized because of the limitations of body mass index (BMI) in correctly characterizing overweight and obese patients, necessitating a better evaluation of nutritional status. The aim of this study was to assess nutritional status, BMI, and significance in terms of HF survival. Anthropometry and biochemical nutritional markers were assessed in 55 HF patients. Undernourishment was defined as the presence of ≥2 of the following indexes below the normal range: triceps skinfold, subscapular skinfold, arm muscle circumference, albumin, and total lymphocyte count. Patients were also stratified by BMI and followed for a median of 26.7 months. Across BMI strata, no patient was underweight, 31% were normal weight, 42% were overweight, and 27% were obese. Undernourishment was present in 53% of normal-weight patients, 22% of overweight patients, and none of the obese patients (p = 0.001). Undernourished patients had significantly higher mortality (p = 0.009) compared to well-nourished patients. In multivariate analysis, only undernutrition (hazard ratio 3.149, 95% confidence interval 1.367 to 7.253), New York Heart Association functional class (hazard ratio 3.374, 95% confidence interval 1.486 to 7.659), and age (hazard ratio 1.115, 95% confidence interval 1.045 to 1.189) remained in the model. Among nutritional indicators, subscapular skinfold was the best predictor of mortality; patients with subscapular skinfold in the fifth percentile had higher mortality (p = 0.0001). In conclusion, BMI does not indicate true nutritional status in HF. Classifying patients as well nourished or undernourished may improve risk stratification.

Usefulness of clinical and NT-proBNP monitoring for prognostic guidance in destabilized heart failure outpatients.

AIMS: To study the relative prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) monitoring in addition to clinical disease severity scores (CDSSs) in outpatients with destabilized heart failure (HF). METHODS AND RESULTS: Seventy-one outpatients with recently destabilized HF were recruited. At baseline, and at all following visits, a CDSS based on Framingham criteria was obtained, and NT-proBNP levels were measured in a blind fashion. CDSS did not correlate with NT-proBNP levels at any time (P > 0.1), although their relative changes correlated during follow-up (P < 0.001). Forty patients (56%) had clinical events (cardiovascular death and/or HF hospitalization) within 1 year of follow-up. Changes in CDSS from baseline were not predictive of subsequent events (P > 0.1 for all visits), whereas changes in NT-proBNP levels were predictive at several time points: week 2 (P = 0.005), week 3 (P = 0.037), week 4 (P = 0.015), and 6 months (P = 0.026). A change in NT-proBNP levels at follow-up week 2 (%) added independent prognostic information (P < 0.001, HR 0.982, 95% CI 0.972-0.992) to baseline CDSS (P = 0.002, HR 2.05, 95% CI 1.290-3.266), age (P = 0.007, HR 1.034, 95% CI 1.009-1.059), and left ventricular ejection fraction (P = 0.013, HR 0.942, 95% CI 0.898-0.987). CONCLUSION: Serial monitoring for per cent change in NT-proBNP concentrations offers superior prognostic information to clinical assessment among outpatients with recent destabilized HF.

Characterization of periodic and non-periodic breathing pattern in chronic heart failure patients.

Periodic breathing (PB) has a high prevalence in chronic heart failure (CHF) patients with mild to moderate symptoms and poor ventricular function. This work proposes the analysis and characterization of the respiratory pattern to identify periodic breathing pattern (PB) and non-periodic breathing pattern (nPB) through the respiratory flow signal. The respiratory pattern analysis is based on the extraction and the study of the flow envelope signal. The flow envelope signal is modelled by an autoregressive model (AR) whose coefficients would characterize the respiratory pattern of each group. The goodness of the characterization is evaluated through a linear and non linear classifier applied to the AR coefficients. An adaptive feature selection is used before the linear and non linear classification, employing leave-one-out cross validation technique. With linear classification the percentage of well classified patients (8 PB and 18 nPB patients) is 84.6% using the statistically significant coefficients whereas with non linear classification, the percentage of well classified patients increase to more than 92% applying the best subset of coefficients extracted by a forward selection algorithm.

Serial NT-proBNP monitoring and outcomes in outpatients with decompensation of heart failure.

BACKGROUND: NT-proBNP is useful for heart failure (HF) diagnosis and prognosis. We examined the value of serial NT-proBNP monitoring to predict outcomes in decompensated HF patients attending a structured HF clinic. METHODS: Patients with decompensation of established optimally treated HF, not requiring emergency hospital admission, were enrolled in the study. Patients received intensive follow-up weekly during 4 weeks and at 3 months in specialist HF clinics. Serial NT-proBNP concentrations were measured at each visit. Primary endpoint was cardiovascular death and hospital admission for HF at 3 months. RESULTS: Fifty-nine patients were enrolled (60+/-14 years, LVEF 27+/-9%) and 39% had a primary endpoint during follow-up. Baseline NT-proBNP concentration (in ng/L) was 7050+/-6620, and did not differ significantly in patients with and without events (p=0.22). Patients without events showed marked NT-proBNP reduction at week-1 (30% reduction), week-2 (36% reduction), week-3 (34% reduction) and week-4 (37% reduction). By contrast, patients with events showed no significant NT-proBNP reduction during follow-up. Using a general linear model, the relative NT-proBNP reductions (%) at weeks 1-4 were predictors of adverse events (p=0.004, p<0.001, p=0.001 and p=0.03, respectively). In a stepwise multiple Cox regression analysis, NT-proBNP relative reduction (in %) at week 2 was a strong predictor of no events during follow-up (OR 0.79, 95% CI 0.70-0.88, p<0.001). CONCLUSIONS: Serial NT-proBNP monitoring in decompensated HF patients seen in a structured in-hospital HF clinic predicts cardiovascular events during follow-up. NT-proBNP may be useful in an outpatient basis to identify patients at high risk needing more aggressive therapy.