Clinical and Pathophysiologic Insights of Free triiodothyronine/Free thyroxine Ratio in Patients with Heart Failure with Preserved Ejection Fraction: Data from the NETDiamond Cohort.

BACKGROUND: Thyroid dysfunction is common in patients with heart failure (HF). Impaired conversion of free T4 (FT4) into free T3 (FT3) is thought to occur in these patients, decreasing the availability of FT3 and contributing to HF progression. In HF with preserved ejection fraction (HFpEF), it is not known whether changes in conversion of thyroid hormones (THs) are associated with clinical status and outcomes. OBJECTIVES: The objective of this study was to evaluate the association of FT3/FT4 ratio and TH with clinical, analytical, and echocardiographic parameters, as well as their prognostic impact in individuals with stable HFpEF. METHODS: We evaluated 74 HFpEF participants of the NETDiamond cohort without known thyroid disease. We performed regression modeling to study the associations of TH and FT3/FT4 ratio with clinical, anthropometric, analytical, and echocardiographic parameters, and survival analysis to evaluate associations with the composite of diuretic intensification, urgent HF visit, HF hospitalization, or cardiovascular death over a median follow-up of 2.8 years. RESULTS: The mean age was 73.7 years and 62% were men. The mean FT3/FT4 ratio was 2.63 (standard deviation: 0.43). Subjects with lower FT3/FT4 ratio were more likely to be obese and have atrial fibrillation. Lower FT3/FT4 ratio was associated with higher body fat (ß = -5.60 kg per FT3/FT4 unit, p = 0.034), higher pulmonary arterial systolic pressure (PASP) (ß = -10.26 mm Hg per FT3/FT4 unit, p = 0.002), and lower left ventricular ejection fraction (LVEF) (ß = 3.60% per FT3/FT4 unit, p = 0.008). Lower FT3/FT4 ratio was associated with higher risk for the composite HF outcome (HR = 2.50, 95% CI: 1.04-5.88, per 1-unit decrease in FT3/FT4, p = 0.041). CONCLUSIONS: In patients with HFpEF, lower FT3/FT4 ratio was associated with higher body fat, higher PASP, and lower LVEF. Lower FT3/FT4 predicted a higher risk of diuretic intensification, urgent HF visits, HF hospitalization, or cardiovascular death. These findings suggest that decreased FT4 to FT3 conversion might be a mechanism associated with HFpEF progression.

Prognostic impact of neurohormonal modulation in very old patients with chronic heart failure.

BACKGROUND: A gap in evidence exists concerning the survival-benefit of neurohormonal blockade in older patients with chronic heart failure (HF). The purpose of our study was to investigate the neurohormonal modulation therapy in older HF patients. METHODS: We retrospectively analysed data on chronic HF patients with systolic dysfunction from January 2012 to May 2018 at a central tertiary academic hospital in Porto, Portugal. Very old (VO) patients were those ≥80 years. Endpoint under analysis: all-cause mortality; patients were followed until January 2021. The prognostic impact of beta-blockers (BBs) and renin-angiotensin system inhibitors (RASi) use was assessed with a Cox-regression analysis adjusting for confounders. RESULTS: We studied 934 patients, 65.5% male; 45.3% had ischemic HF. BBs were used in 92.2% and RASi in 83.5%; 255 (27.3%) were VO patients. VO more often presented co-morbidities, were more symptomatic, presented worse renal function and higher BNP levels. BB prescription was similar in VO and non-VO patients, however RASi were less used in VO: 74.9% versus 86.7%, respectively. During a median follow-up of 47 months, 479 (51.3%) patients died: 71.4% among VO versus 43.7% in non-VO. BBs increased survival both in non-VO and VO-multivariate adjusted HRs of 0.57 (95% CI: 0.38-0.85) and 0.59 (0.36-0.97), respectively. A survival-benefit was also observed with RASi-adjusted HR of 0.71 (0.50-1.01) and 0.59 (0.42-0.83) in non-VO and VO. CONCLUSIONS: VO patients with chronic HF with systolic dysfunction have a very ominous outcome. Neurohormonal modulation therapy appears to portend survival-benefit also in this particularly vulnerable subgroup of patients.

Elevated Cystatin C Predicts Higher Mortality in Chronic Heart Failure Independently of Renal Function.

INTRODUCTION: Cystatin C (CysC) is a known prognostic marker in cardiovascular diseases and its role in acute heart failure (HF) has been documented. METHODS: We prospectively recruited HF patients followed in a HF clinic. Inclusion criteria: HF diagnosed ≥6 months, optimized evidence-based therapy, and ejection fraction <40% (Heart Failure with reduced ejection fraction). Exclusion criteria: renal replacement therapy and hospitalizations or therapeutic adjustments in the previous 2 months. A venous blood sample and 24-hour urine were collected. Follow-up: 5 years; endpoint: all-cause mortality. CysC was measured and creatinine clearance (CrCl) was calculated using 24-hour urine creatinine excretion. A Receiver operating characteristic curve was used to assess association of CysC with 5-year mortality. The prognostic role of CysC was determined using Cox-regression analysis. The multivariate model included CrCl (24-hour urine). RESULTS: We evaluated 215 chronic stable Heart Failure with reduced ejection fraction patients. Mean age was 68 years, 72.1% were male. Median CysC = 1.15 mg/L, creatinine = 1.20 mg/dL, and CrCl = 63.6 mL/min. During follow-up, 103 (47.9%) patients died. The area under the curve for CysC in predicting mortality was 0.77 (0.70-0.83). Best cut-off value for death prediction = 1.00 mg/L with a sensitivity = 83.5%, specificity = 56.2%, positive predictive value = 63.7%, and negative predictive value = 78.7%. Multivariate-adjusted (age-, B-type natriuretic peptide-, evidence-based therapy, New York Heart Association class, and CrCl) 5-year mortality Hazard ratio = 2.40 (95% Confidence interval, 1.25-4.61), P value = 0.008 when CysC ≥1.00 mg/L. CONCLUSIONS: Patients with CysC <1.00 mg/L have almost 80% probability of being alive at 5 years; If CysC ≥1.00 mg/L, there is almost 2.5-fold higher death risk independently of B-type natriuretic peptide and CrCl.

Prognostic impact of red blood cell distribution width in chronic heart failure patients with left ventricular dysfunction.

AIMS: Red blood cell (RBC) distribution width (RDW) measures RBC variations in size. Higher RDW values have been associated with poor outcome in acute heart failure (HF). We aimed to assess the prognostic impact of the RDW in chronic HF. METHODS: We retrospectively analysed a cohort of chronic HF patients with left ventricular systolic dysfunction followed in our HF clinic between January 2012 and May 2018. Patients with missing data concerning RDW were excluded. Patients were categorized according to RDW tertiles: ≤13.5%; between 13.5 and 14.7%; and >14.7%. Patients were followed until January 2021; all-cause mortality was the end point analysed. The association of RDW with all-cause mortality was assessed with a Cox-regression analysis. Two multivariate models were built. RESULTS: We studied 860 chronic HF patients, 66.4% males, mean age 70 (standard deviation, SD 13) years. Patients were followed for a median of 49 (29-82) months. During this period, 423 (49.2%) patients died. Mortality increased with increasing RDW tertiles. Patients with RDW >14.7% had a HR of mortality of 1.95 (1.47-2.58), p < 0.001 (model 1) and of 1.81 (1.35-2.41), p < 0.001 (model 2) when compared with those with RDW ≤13.5. Patients in the second RDW tertile had an all-cause death HR of 1.47 (1.12-1.93) and of 1.44 (1.09-1.90) in models 1 and 2, respectively. CONCLUSIONS: Chronic HF patients with RDW values >14.7% presented an almost 2-fold higher risk of dying in the long term than those with RDW <13.5%. RDW is a widely available and easily measured parameter that can help clinicians in the risk stratification of chronic HF patients.

Natriuretic peptides in aortic stenosis.

Aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries. Diagnosis, risk stratification and monitoring are usually based on clinical and echocardiographic parameters. Complementary methods are needed to improve management and outcome, particularly in patients with severe asymptomatic AS, whose management remains controversial. Natriuretic peptides (NPs) have established value as biomarkers in heart failure, coronary heart disease and pulmonary hypertension. This review discusses the usefulness and prognostic value of natriuretic peptides in AS. B-type natriuretic peptide (BNP) and its prohormone (NT-proBNP) correlate with disease severity, development of symptoms and prognosis, but before they can be routinely used in clinical practice, additional prospective studies are needed.

Relaxin-2, pathophysiological insights and outcomes in heart failure with preserved ejection fraction: Findings from the NETDiamond cohort.

AIMS: The role of relaxin-2 as a circulating marker in heart failure (HF) with preserved ejection fraction (HFpEF) is poorly understood. We aimed to characterize relaxin-2 circulating levels in a population of chronic HFpEF patients and their association with long-term prognosis. METHODS: Relaxin-2 serum levels were measured in 85 chronic HFpEF patients from a prospective cohort study (NETDiamond). Clinical, imaging, and analytical data were compared across relaxin-2 tertiles. The primary outcome was a composite of cardiovascular death, HF hospitalisation, acute HF episode or diuretic intensification and the secondary outcome a composite of cardiovascular death and total HF hospitalisations. Cox regression and negative binomial models were used to assess the relation between relaxin-2 and the outcomes. RESULTS: Relaxin-2 levels were positively associated with left atrial volume, left ventricular mass and peripheral oedema, and negatively associated with ischemic heart disease and statin use. Higher relaxin-2 levels were associated with an increased risk of primary outcome, even after adjustment for age, B-type natriuretic peptide (BNP) and glomerular filtration rate (eGFR) (adjusted HR = 2.80, 95%CI 1.4-7.3, p = 0.034 for tertile 3). They were also associated with the occurrence of the secondary outcome (Incidence Rate Ratio = 5.28, 95%CI 1.2-23.2, p = 0.027), but this significance was lost when simultaneously adjusted for BNP and eGFR. CONCLUSION: In chronic HFpEF patients, higher relaxin-2 circulating levels were associated with left chambers remodelling, congestion, and adverse prognosis. These findings support a potential role for relaxin-2 as a pathophysiological agent and as a circulating biomarker in HFpEF.

The ratio of furosemide dosage to urinary sodium concentration predicts mortality in patients with chronic stable heart failure.

INTRODUCTION: The urinary sodium (UNa) concentration is associated with outcomes in patients with acute heart failure (HF). Its impact in individuals with chronic HF is unknown. OBJECTIVES: This study examined the combined effect of diuretic dosage and UNa concentration in chronic HF. PATIENTS AND METHODS: The research sample for this retrospective cohort study consisted of ambulatory patients receiving optimized therapy and followed in an HF clinic. The patients were recruited between 2009 and 2012. The exclusion criteria were therapeutic adjustments or hospital admissions in the previous 2 months and renalreplacement therapy. The patients were followed for 5 years; the endpoint was all­cause mortality. The association between the ratio of furosemide dosage to UNa concentration and 5­year mortality was studied using a receiver operating characteristic (ROC) curve. The  patients were cross­classified according to daily furosemide dosage (with the cutoff set at 80 mg) and UNa concentration (80 mEq/l). Multivariable Cox regression analysis was used to assess the prognostic impact of the ratio. RESULTS: We analyzed 283 patients with chronic HF (70.3% male; mean age, 69 years). During follow­up, 134 patients died. The median furosemide dosage was 80 mg/day and the mean UNa concentration was 85 mEq/l. Based on the ROC curve, the best cutoff for the ratio of daily furosemide dosage to UNa concentration was 0.8. Patients with a ratio of 0.8 or higher had an adjusted hazard ratio for 5­year mortality of 2.85 (95% CI, 1.78-4.58). Patients with a UNa excretion rate of less than 80 mEq/l who wereadministered 80 mg or more of furosemide per day were found to have a worse prognosis (HR, 4.15; 95% CI, 2.31-7.45) when compared with those with a UNa excretion rate of 80 mEq/l or more and less than 80 mg furosemide per day. CONCLUSIONS: Combining the diuretic dosage and measurement of UNa excretion can be used to refine risk stratification in chronic HF. The furosemide­to­UNa ratio can be a surrogate marker for diuretic resistance and has a prognostic impact in chronic HF.

Neurovascular Coupling Impairment in Heart Failure with Reduction Ejection Fraction.

The hemodynamic consequences of a persistent reduced ejection fraction and unknown cardiac output on the brain have not been thoroughly studied. We sought to explore the status of the mechanisms of cerebrovascular regulation in patients with heart failure with reduced (HFrEF) and recovered (HFrecEF) ejection fraction. We monitored cerebral blood flow velocity (CBFV) with transcranial Doppler and blood pressure. Cerebral autoregulation, assessed by transfer function from the spontaneous oscillations of blood pressure to CBFV and neurovascular coupling (NVC) with visual stimulation were compared between groups of HFrEF, HFrecEF and healthy controls. NVC was significantly impaired in HFrEF patients with reduced augmentation of CBFV during stimulation (overshoot systolic CBFV 19.11 ± 6.92 vs. 22.61 ± 7.78 vs. 27.92 ± 6.84, p = 0.04), slower upright of CBFV (rate time to overshoot: 1.19 ± 3.0 vs. 3.06 (4.30) vs. 2.90 ± 3.84, p = 0.02); p = 0.023) and reduced arterial oscillatory properties (natural frequency 0.17 ± 0.06 vs. 0.20 ± 0.09 vs. 0.24 ± 0.07, p = 0.03; attenuation 0.34 ±0.24vs 0.48 ± 0.35 vs. 0.50 ± 0.23, p = 0.05). Cerebral autoregulation was preserved. The neurovascular unit of subjects with chronically reduced heart pumping capability is severely dysfunctional. Dynamic testing with transcranial Doppler could be useful in these patients, but whether it helps in predicting cognitive impairment must be addressed in future prospective studies.

Prognostic value of high-sensitivity C-reactive protein in heart failure: a systematic review.

BACKGROUND: Several studies have suggested that high-sensitivity C-reactive protein (hsCRP) is a strong independent predictor of acute myocardial infarction and cardiovascular death. In the specific heart failure (HF) context, a low-grade inflammatory state can contribute to HF progression. AIMS: To perform a systematic review on the current knowledge about low-grade inflammation, as assessed by hsCRP, in the prediction of HF in general and in high-risk populations as well as its prognostic value in established HF. METHODS: We used a computerized literature search in the Medline database using the following key words: C-Reactive Protein, Heart Failure, Cardiomyopathy, Cardiac Failure, Prognosis, and Death. Articles were selected if they had measurements of hsCRP in different patient samples and reference to outcomes in terms of morbidity and mortality. RESULTS: hsCRP is associated with incident HF in general and high-risk populations and provides prognostic information in HF patients. In almost all studies, the association of hsCRP with clinical events was independent of other baseline variables known to influence morbidity and mortality. Very different cutoffs have been proposed in each context across studies. CONCLUSIONS: The prognostic power of hsCRP, whether we consider incident HF or adverse outcomes in established HF, is consistent in different patient populations.

The cyclic guanosine monophosphate/B-type natriuretic peptide ratio and mortality in advanced heart failure.

AIMS: Attenuation of the effects of natriuretic peptides has been demonstrated in animal models but studies in humans are scarce, particularly concerning renal attenuation. We investigated the attenuation of B-type natriuretic peptide (BNP) in chronic advanced heart failure (HF). METHODS AND RESULTS: We included 62 outpatients with HF and severe left ventricular systolic dysfunction. Cases had at least one hospital admission or emergency department visit for acute HF in the previous year and were in NYHA class III/IV despite optimized therapy. The individual age- and sex-matched controls were symptomatically controlled (NYHA I and II). We collected 24 h urine and a blood sample from all patients. Plasma BNP and plasma (pcGMP) and urine cyclic guanosine monophosphate (ucGMP) were measured. Patients were followed for 3 months for hospital admission or all-cause death. ucGMP to plasma BNP (ucGMP/BNP) ratio was attenuated in cases vs. controls [median (IQR): 8354 (4293-16,456) vs. 12,693 (6896-22,851)]. There were no differences in pcGMP to BNP (pcGMP/BNP) ratio or urine cGMP excretion. Patients with worse outcome had lower pcGMP/BNP [260 (86-344) vs. 381 (244-728) in patients without adverse outcome events] and lower ucGMP/BNP [4146 (2207-9363) vs. 10,922 (7495-19,971)]. CONCLUSION: Renal NP's second messenger production is attenuated in advanced HF. Patients with worse outcome have lower ucGMP/BNP and pcGMP/BNP ratios.

Adiponectin is increased in cardiac cachexia irrespective of body mass index.

AIMS: Cardiac cachexia (CC) is a complication of chronic heart failure (CHF). Little is known about the mechanisms leading to CC. Adiponectin, leptin, and ghrelin are important regulators of energy metabolism and body weight. Previous studies of CHF and CC had great differences in body mass index (BMI) between cachectic and non-cachectic patients. To assess serum adiponectin, leptin, and ghrelin concentrations in cachectic and non-cachectic patients. METHODS AND RESULTS: We conducted a case-control study in CHF patients matched for BMI. Cases (n = 33) were cachectic patients with unintentional weight loss of > or = 7.5% of the previous baseline weight. Controls (n = 33) had no history of weight loss and were individually matched with cases for age, sex, and BMI. Cachectic patients had significantly higher adiponectin levels than controls: 25.0 +/- 12.3 vs. 14.7 +/- 8.8 microg/mL (P = 0.002). Leptin concentration was lower in the cachectic group: 7.5 (IQR 4.0-10.8) vs. 8.0 (IQR 7.1-10.5) ng/mL. Differences in leptin lost significance once adjusted for fat mass. Adiponectin remained higher in cachectics after such adjustment. Ghrelin was not significantly different between groups. Adiponectin correlated positively with weight loss and BNP. CONCLUSION: Cachexia in CHF was associated with an increase in adiponectin, irrespective of BMI. This suggests a role of adiponectin in the wasting process of cachectic patients.

An Unusual Case of Tricuspid Stenosis.

Tricuspid stenosis is an uncommon valvular abnormality commonly associated with other valvular lesions. Ebstein's anomaly is a rare congenital heart malformation characterized primarily by abnormalities of the tricuspid valve and right ventricle. Endomyocardial fibrosis is a restrictive cardiomyopathy observed in tropical and subtropical regions. It may cause right ventricular distortion with apparent apical displacement of the tricuspid valve, mimicking Ebstein's anomaly. Eosinophilia is the most commonly cited aetiological link in endomyocardial fibrosis. Here we report the case of 42-year-old male patient who presented with heart failure and severe tricuspid stenosis where a diagnosis of hypereosinophilic syndrome was also established. This case represented a diagnostic challenge in the search for the definitive cause of the tricuspid stenosis. LEARNING POINTS: Ebstein's anomaly is a rare congenital heart malformation characterized primarily by abnormalities of the tricuspid valve and right ventricle. The tricuspid valve is usually incompetent, and very rarely stenotic.Hypereosinophilic syndromes can be associated with heart damage. The fibrotic stage of eosinophil-mediated heart damage is characterized by altered cardiac function due to either compromise/entrapment of the cordae tendineae and/or restrictive cardiomyopathy.Endomyocardial fibrosis is a restrictive cardiomyopathy observed in tropical and subtropical regions that may be indistinguishable from the Loeffler's endocarditis observed in temperate climates. It may cause right ventricle distortion and apical displacement of the tricuspid valve, mimicking Ebstein's anomaly.

Age affects the prognostic impact of diabetes in chronic heart failure.

AIMS: Increasing age is an established prognostic determinant in chronic heart failure (HF). Diabetes often complicates HF in its course and appears to worsen HF prognosis. A differential impact of diabetes depending on patients' age was not yet studied. We evaluated the impact of diabetes in the mortality of HF patients according to their age. METHODS: We studied a cohort of chronic ambulatory HF patients prospectively recruited. Patients were on optimized evidence-based therapy, and they were excluded if on renal replacement therapy or if they had any therapy modification or hospitalizations in the previous 2 months. Patients were followed for up to 5 years; all-cause mortality was analyzed. Mortality predictors were assessed using a Cox regression. Analysis was stratified according to patient's age: cutoff 75 years. Multivariate models were built. Interaction between diabetes and age was formally tested. RESULTS: We studied 283 chronic HF patients; mean age was 69 years and 70.3% were male; 58.0% had severe systolic dysfunction; 105 (37.1%) were diabetic. In patients with less than 75 years, the coexistence of diabetes predicted a multivariate adjusted 1.98 (95% CI 1.13-3.46) 5-year death risk while in older patients (≥ 75 years) no significant association was reported. Age interacted with the prognostic impact of diabetes, p for interaction = 0.04. CONCLUSIONS: The prognostic impact of diabetes in chronic HF depends on patient's age. In patients < 75 years, the coexistence of diabetes predicts an almost double risk of 5-year mortality; no such association exists in patients with 75 years or above. Diabetes predicts mortality only in younger HF patients.

Amino terminal B-type natriuretic peptide, renal function, and prognosis in acute heart failure: a hospital cohort study.

BACKGROUND: Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable diagnostic and prognostic test in heart failure (HF). Limited information is available concerning its use in patients with renal failure, in whom dependence on renal clearance may negatively affect its performance. METHODS AND RESULTS: We evaluated influence of renal function on NT-proBNP levels and on its prognostic value after hospital discharge in 283 acute HF patients. Admission and discharge NT-proBNP levels were higher in patients with decreased estimated glomerular filtration rate (eGFR). In these patients discharge NT-proBNP above median was associated to occurrence of death or readmission at 6 months (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.27-5.03); in patients with normal eGFR, a trend to this association was found (HR 1.64, CI 0.98-2.76). Decrease in NT-proBNP less than 30% of baseline was associated to outcome in patients with normal eGFR (HR 2.68, CI 1.54-4.68) and decreased eGFR (HR 2.54, CI 1.49-4.33). CONCLUSIONS: Acute HF patients with renal failure have higher NT-proBNP levels than those with normal renal function. Discharge NT-proBNP has long-term prognostic value in HF patients with renal dysfunction. NT-proBNP variations during hospitalization provide additional prognostic information either in patients with normal or reduced eGFR.

Dipeptidyl peptidase-IV in chronic heart failure with reduced ejection fraction.

BACKGROUND: An association between dipeptidyl peptidase-IV (DPP-IV) inhibitors with worse prognosis in HF has been suggested. We aimed to assess the serum DPP-IV levels in chronic stable HF patients and determine their association with prognosis. METHODS AND RESULTS: Chronic stable HF patients with optimized prognostic-modifying therapy were prospectively recruited. EXCLUSION CRITERIA: 1) ejection fraction>50%, 2) hospitalizations or therapeutic adjustments in the previous 2months; 3) patients on renal replacement therapy, and 4) use of DPP-IV inhibitors. A fasting venous blood sample was collected and DPP-IV was measured. Patients were followed-up for 3years and the endpoint studied was all-cause death. Patients' characteristics were compared according to DPP-IV quartiles. A Cox regression analysis was performed and multivariate models were built. The 3rd DPP-IV quartile was the reference category. We studied 264 patients. Mean age: 69 (±13)years, 70.5% were male and 33.7% diabetic. Median (IQR) serum DPP-IV levels were 455.6 (350.0-625.5)ng/mL. DPP-IV had an inverse relationship with age. Patients in 3rd DPP-IV quartile were in lower NYHA classes and had the lowest 3years all-cause mortality. Patients in the 1st DPP-IV quartile had a multivariate adjusted HR of 3-year mortality of 2.62 (95%CI: 1.15-5.95) when compared with reference category and the HR for the 4th quartile was of 3.79 (95%CI: 1.68-8.54). CONCLUSIONS: There is a U-shaped association of serum DPP-IV with mortality in chronic systolic HF patients. Patients in the 3rd DPP-IV quartile have the best multivariate adjusted 3-year survival. DPP-IV inhibition might be harmful in patients with low DPP-IV.

Intraindividual variation of amino-terminal pro-B-type natriuretic peptide levels in patients with stable heart failure.

This study aimed to evaluate how large the variation between measurements of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) can be in patients with clinically stable heart failure (HF). The fluctuation of NT-pro-BNP in patients with HF has not been previously evaluated. Patients with chronic, stable HF were evaluated at 3-week intervals. The relative (percentage of baseline) difference between the 2 NT-pro-BNP measurements and their mean were calculated. In total, 118 double measurements of NT-pro-BNP were obtained. Changes in NT-pro-BNP measurements were determined according to quartiles of mean NT-pro-BNP. The median baseline NT-pro-BNP level was 1,323 pg/ml (25th and 75th percentiles 433 and 2,258), and the median second NT-pro-BNP level was 1,394 pg/ml (25th and 75th percentiles 475 and 2,353) (p = 0.34). Among pairs of measurements in the first quartile (NT-pro-BNP <450 pg/ml), the 5th and 95th percentiles of the distribution of relative differences were -86% and +197%. In the second (450 to 1,300 pg/ml), third (1,300 to 2,300 pg/ml), and fourth (>2,300 pg/ml) quartiles, the 5th and 95th percentiles of relative differences were -42% and +78%, -29% and +38%, and -30% and +37%, respectively, of the baseline values. In conclusion, the results support the clinical use of NT-pro-BNP in the monitoring of patients with HF with NT-pro-BNP levels >1,300 pg/ml. In these patients, variations between 1/3 less and about 40% more can be expected without clinical improvement or deterioration.

Predictors of natriuretic peptide non-response in patients hospitalized with acute heart failure.

Increasing natriuretic peptide (NP) levels are associated with worse heart failure (HF) outcomes. Predictors of NP nonresponse have not been studied. The aim of this study was to identify predictors of nondecreasing NP levels during episodes of acute HF. A retrospective analysis was conducted in patients prospectively included in a registry of acute HF, with the primary diagnosis of acute HF. The objective under analysis was B-type NP (BNP) response, defined as a >30% decrease in BNP during hospitalization. Percentage of BNP variation was calculated as: % BNP variation = [(admission BNP - discharge BNP)/admission BNP] × 100. A logistic regression analysis was performed to study potential predictors of NP nonresponse. A multivariate model was built. A total of 496 patients were studied: 28.2% were considered nonresponders to the implemented HF treatment strategy. Identified predictors of nonresponse were older age, chronic HF, lower admission systolic blood pressure, anemia, renal dysfunction, and lower sodium on admission, as well as lower admission albumin and lower admission total cholesterol. Admission BNP was not a predictor of response. The only identified independent predictor of nonresponse was a low admission total cholesterol level (cutoff 125 mg/dl), with an odds ratio of 2.55 (95% confidence interval 1.59 to 4.11). This remained valid when the analysis was stratified according to admission BNP (cutoff 2,000 pg/ml) and according to statin use. In conclusion, a low admission total cholesterol level was a strong and independent predictor of BNP nonresponse in patients admitted with acute HF. The ability of cholesterol to predict BNP nonresponse was valid for patients with intrinsically low cholesterol and in those with statin-induced low cholesterol.

Low prealbumin is strongly associated with adverse outcome in heart failure.

OBJECTIVE: Prealbumin is one of the best indicators of nutritional status. We previously showed that prealbumin predicted in-hospital mortality in heart failure (HF) patients. We evaluated if a low discharge prealbumin after admission with acute HF would predict morbidity and mortality. METHODS: We conducted a prospective observational study. Patients admitted with a primary diagnosis of HF were studied. Follow-up was up to 6 months. Endpoints analysed were: all-cause and HF-death; all-cause and worsening HF hospitalisation. Patients with discharge prealbumin ≤15.0 mg/dL and those with prealbumin >15 mg/dL were compared. A Cox-regression analysis was used to evaluate the prognostic impact of low prealbumin. RESULTS: We studied 514 patients. Mean age was 78 years and 45.7% were male. During follow-up, 101 patients died (78 for HF) and 209 patients were hospital readmitted (140 for worsening HF). Median prealbumin was 20.1 (15.3-25.3) mg/dL. Patients with lower prealbumin were more often women, older aged and with non-ischaemic HF; they had lower albumin, haemoglobin and total cholesterol; and higher glomerular filtration rate, C-reactive protein, B-type natriuretic peptide and length of hospital stay. Lower prealbumin associated with less ß-blocker and statin use. Patients with discharge prealbumin ≤15 mg/dL had a multivariate adjusted HR of 6-month all-cause and HF death of 1.67 (1.00 to 2.80) and 2.12 (1.19 to 3.79) respectively and of all-cause and HF readmission of 1.47 (1.01 to 2.14) and 1.58 (1.01 to 2.47). CONCLUSIONS: Patients with discharge prealbumin ≤15 mg/dL have an higher risk of 6 months morbidity and mortality. The unbalance between protein-energy demands and its availability predicts ominous HF outcome.

Statin-induced low cholesterol is not associated with poor outcome in chronic heart failure.

BACKGROUND: Low cholesterol levels are associated with a worse outcome in patients with heart failure (HF). Use of statins in HF remains controversial. We aimed to assess whether the prognosis of patients with intrinsically low cholesterol levels differed from that of those with pharmacologically induced low cholesterol. MATERIALS AND METHODS: We conducted a retrospective cohort study on 464 ambulatory patients attending a specialized HF clinic. Patients were cross-classified according to statin therapy and admission total cholesterol level (low cholesterol <150 mg/dL and cholesterol ≥150 mg/dL): (1) low total cholesterol level on statin therapy; (2) low total cholesterol level not taking statins; (3) cholesterol ≥150 mg/dL on statin therapy; and (4) cholesterol ≥150 mg/dL not on statin therapy. Patients were followed up to 5 years and the outcome was all-cause death. A Cox regression analysis was used in prognosis assessment. RESULTS: Almost two thirds of the patients were men and the median population age was 69 years; 22.8% of the patients had preserved ejection fraction and 43.5% severe systolic dysfunction. The patients with an intrinsically low cholesterol had a hazard ratio of all-cause death up to 5 years of 2.38 (1.08-7.14) compared to those with low cholesterol induced by statin use. This association was independent of other variables associated with outcome. CONCLUSIONS: Patients with HF with instrisically low cholesterol levels have a double risk of death up to 5 years compared to patients with pharmacologically induced low cholesterol. Clinicians should not limit the use of statins by fear of lowering the cholesterol levels.