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Purpose: Heart valve calcification (VC) is associated with increased cardiovascular risk, but the hemodynamic and functional profile of patients affected by VC has not been fully explored., Methods: The study population was formed by consecutive unselected patients included in seven echocardiographic laboratories in a 2-week period. A comprehensive echocardiographic examination was performed. VC was defined by the presence of calcification on at least one valve., Results: Population was formed of 1098 patients (mean age 65 ± 15 years; 47% female). VC was present in 31% of the overall population. Compared with subjects without VC, VC patients were older (60 ± 14 vs 75 ± 9; P < .0001), had more hypertension (40% vs 57%; P = .0005), diabetes (11% vs 18%; P = .002), coronary artery disease (22% vs 38%; P = .04), and chronic kidney disease (4% vs 8%; P = .007). Furthermore, VC patients had lower ejection fraction (55 ± 14 vs 53 ± 25; P < .0001), worse diastolic function (E/e' 8.5 ± 4.6 vs 13.0 ± 7.1; P < .0001) and higher pulmonary artery pressure (29 ± 9 vs 37 ± 12; P < .0001). The association between VC and EF was not independent of etiology (p for VC 0.13), whereas the association with E/e' and PASP was independent in a full multivariate model (P < .0001 and P = .0002, respectively)., Conclusion: Heart valve calcification patients were characterized by a worse functional and hemodynamic profile compared to patients with normal valve. The association between VC and diastolic function and PASP were independent in comprehensive multivariate models., (© 2021 Wiley Periodicals LLC.)

Background: Left ventricular hypertrophy (LVH) may reflect a wide variety of physiologic and pathologic conditions. Thus, it can be misleading to consider all LVH to be homogenous or similar. Refined 4-group classification of LVH based on ventricular concentricity and dilatation may be identified. To determine whether the 4-group classification of LVH identified distinct phenotypes, we compared their association with various noninvasive markers of cardiac stress., Methods: Cohort of unselected adult outpatients referred to a seven tertiary care echocardiographic laboratory for any indication in a 2-week period. We evaluated the LV geometric patterns using validated echocardiographic indexation methods and partition values., Results: Standard echocardiography was performed in 1137 consecutive subjects, and LVH was found in 42%. The newly proposed 4-group classification of LVH was applicable in 88% of patients. The most common pattern resulted in concentric LVH (19%). The worst functional and hemodynamic profile was associated with eccentric LVH and those with mixed LVH had a higher prevalence of reduced EF than those with concentric LVH (P < .001 for all)., Conclusions: The new 4-group classification of LVH system showed distinct differences in cardiac function and noninvasive hemodynamics allowing clinicians to distinguish different LV hemodynamic stress adaptations in patients with LVH., (© 2018 Wiley Periodicals, Inc.)

Background: In-hospital worsening heart failure (WHF) is predictive of worse post-discharge outcomes and has been recently used as an endpoint in clinical trials in acute heart failure (AHF)., Methods: We described the clinical and prognostic significance of WHF in consecutive patients hospitalized for AHF at our institute. WHF was defined as worsening signs and symptoms of HF requiring treatment intensification. We compared WHF events by day 7 (early WHF) with WHF occurring at any time during admission. The primary endpoint was cardiovascular (CV) death and HF rehospitalizations through day 60., Results: We included 387 consecutive patients. Median length of stay was 11days (interquartile range 8-18days). Forty-five patients (11.6%) had WHF, HF rehospitalization, or death through day 7 whereas 90 (23.3%) had WHF or died at any time during initial hospitalization. Patients with WHF occurring any time during admission were more symptomatic, had lower systolic blood pressure, worse renal function, and higher troponins at baseline. Both early WHF and WHF at any time during hospitalization were associated with a longer length of stay and higher CV death and HF rehospitalization rates at day 60, but only WHF at any time was associated with all-cause death at day 180 (adjusted HR 2.42 95% CI 1.30, 4.52; p=0.0055) and with all-cause death any time during the follow-up period (adjusted HR 1.60 95% CI 1.02, 2.53; p=0.0425)., Conclusions: Our study confirms the prognostic significance of WHF and shows the independent prognostic value of WHF also for long-term mortality when assessed throughout hospitalization., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In patients with acute heart failure, high levels of N-terminal-pro-brain natriuretic peptide (NT-proBNP) at discharge are associated with worse outcomes. We hypothesized that NT-proBNP-guided therapy may improve prognosis., Methods and Results: Two hundred and seventy-one consecutive patients, admitted for acute heart failure, were prospectively randomized to NT-proBNP-guided therapy or control group. The NT-proBNP-guided therapy group underwent medical treatment intensification when predischarge NT-proBNP was at least 3000 pg/ml. The primary endpoint was cardiovascular death or cardiovascular rehospitalization at day 182. The secondary endpoints were all-cause death, cardiovascular death, cardiovascular rehospitalization, heart failure rehospitalization, and cardiovascular death or heart failure rehospitalization at day 182. Treatment intensification in the NT-proBNP-guided therapy group regarded mainly diuretics. The NT-proBNP strategy was not associated with a significant reduction of the primary endpoint [43% intervention vs. 39% controls, hazard ratio 1.22 (0.84, 1.76), P = 0.305] and of any secondary endpoint. The change of NT-proBNP from predischarge to discharge was associated with the risk of cardiovascular death or cardiovascular rehospitalization through day 182, even after multivariable adjustment., Conclusion: NT-proBNP-guided therapy resulted mainly in an increase of diuretics in acute setting and compared with clinical evaluation alone did not improve prognosis. However, the reduction of NT-proBNP at discharge was an independent predictor of outcomes.

Objectives: The aim of this study was to analyze the prognostic value and attainability of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in young and elderly acute decompensated heart failure (ADHF) patients., Background: Less-effective NT-proBNP-guided therapy in chronic heart failure (HF) has been reported in elderly patients. Whether this can be attributed to differences in prognostic value of NT-proBNP or to differences in attaining a prognostic value is unclear. The authors studied this question in ADHF patients., Methods: Our study population comprised 7 ADHF cohorts. We defined absolute (<1,500 ng/l, <3,000 ng/l, <5,000 ng/l, and <15,000 ng/l) and relative NT-proBNP discharge cut-off levels (>30%, >50%, and >70%). Six-month all-cause mortality after discharge was studied for each level in Cox regression analyses, and compared between elderly (age >75 years) and young patients (age ≤75 years). Thereafter, we compared percentages of elderly and young patients attaining NT-proBNP levels (= attainability)., Results: A total of 1,235 patients (59% male, 45% >75 years of age) was studied. Admission levels of NT-proBNP were significantly higher in elderly versus younger patients. The prognostic value of absolute and relative NT-proBNP levels was similar in elderly and young patients. Attainability was significantly lower in elderly patients for all absolute levels and a >50% relative reduction, but not for >30% and >70%. For absolute levels, attainability differences between age groups were decreased to a large extent after correction for admission NT-proBNP and anemia at discharge. For relative levels, attainability differences disappeared after correction for HF etiology and anemia at discharge., Conclusions: In young and elderly ADHF patients, it is not the prognostic value of absolute and relative NT-proBNP levels that is different, but the attainability of these levels that is lower in the elderly. This can largely be attributed to factors other than age., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: NT-proBNP is a strong predictor for readmissions and mortality in acute decompensated heart failure (ADHF) patients. We assessed whether absolute or relative NT-proBNP levels should be used as pre discharge treatment target., Methods and Results: Our study population was assembled from seven ADHF cohorts. We defined absolute (<1500, <3000, <5000, and <15 000 ng/L) and relative NT-proBNP targets (>30, >50, and >70%). Population attributable risk fraction (PARF) is the proportion of all-cause 6-month mortality in the population that would be reduced if all patients attain the NT-proBNP target. PARF was determined for each target as well as the percentage of patients attaining the NT-proBNP target. Attainability was investigated by logistic regression analysis. A total of 1266 patients [age 74 (64-80), 60% male] was studied. For every absolute NT-proBNP level, a corresponding percentage reduction was found that resulted in similar PARFs. The highest PARF (∼60-70%) was observed for <1500 or >70%, but attainability was low (27% and 22%, respectively). The strongest predictor for not attaining these targets was admission NT-proBNP. In admission NT-proBNP tertiles, PARFs were significantly different for absolute, but not for relative targets., Conclusion: In an ADHF population, pre-discharge absolute or relative NT-proBNP targets may both be useful as they have similar effects on PARF. However, depending on admission NT-proBNP, absolute targets show varying PARFs, while PARFs for relative targets were similar. A relative target is predicted to reduce mortality consistently across the whole spectrum of ADHF patients, while this is not the case using a single absolute target., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Objective: Chronic heart failure (CHF) is characterized by several micronutrient deficits. Amino acid supplementation may have a positive effect on nutritional and metabolic status in patients with CHF. Levo-carnosine (β-alanyl-L-histidine) is expressed at a high concentration in myocardium and muscle. Preliminary studies with L-carnosine in healthy individuals have suggested a potential role in improving exercise performance. To our knowledge, no study has been conducted in patients with heart failure. The aim of this study was to test the oral supplementation of L-carnosine and its effects on quality of life and exercise performance in patients with stable CHF., Methods: Fifty patients with stable CHF and severe left-ventricular systolic dysfunction on optimal medical therapy were randomized 1:1 to receive oral orodispersible L-carnosine (500 mg OD) or standard treatment. Left-ventricular ejection fraction (LVEF) was measured by echocardiography. Cardiopulmonary stress test, 6-minute walking test (6 MWT) and quality-of-life (visual analog scale score and the EuroQOL five dimensions questionnaire [EQ-5D]) were performed at baseline and after 6 mo., Results: Patients receiving orodispersible L-carnosine had an improvement in 6 MWT distance (P = 0.014) and in quality-of-life (VAS score) (P = 0.039) between baseline and follow-up. Compared with controls, diet supplementation with orodispersible L-carnosine was associated with an improvement in peakVO2 (P < 0.0001), VO2 at anaerobic threshold, peak exercise workload, 6 MWT and quality-of-life assessed by the EQ-5D test and the VAS score., Conclusion: This study suggests that L-carnosine, added to conventional therapy, has beneficial effects on exercise performance and quality of life in stable CHF. More data are necessary to evaluate its effects on left-ventricular ejection fraction and prognosis in CHF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Previous heart failure (HF) trials suggested that age influences patient characteristics and outcome; however, under-representation of elderly patients has limited characterization of this cohort. Whether standard prognostic variables have differential utility in various age groups is unclear., Methods and Results: The PROTECT trial investigated 2033 patients (median age 72 years) with acute HF randomized to rolofylline or placebo. Patients were divided into five groups based on the quintiles of age: ≤59, 60-68, 69-74, 75-79, and ≥80 years. Baseline characteristics, medications, and outcomes (30-day death or cardiovascular/renal hospitalization, and death at 30 and 180 days) were explored. The prognostic utility of baseline characteristics for outcomes was investigated in the different groups and in those aged <80 years vs. ≥80 years. With increasing age, patients were more likely to be women with hypertension, AF, and higher EF. Increased age was associated with increased risk of 30- and 180-day outcomes, which persisted after multivariable adjustment (hazard ratio for 180-day death = 1.17; 95% confidence interval 1.11-1.24 for each 5-year increase). The prognostic utility of baseline characteristics such as previous HF hospitalization and serum sodium, systolic blood pressure, and NYHA class was attenuated in the elderly for the endpoint of 180-day mortality. An increase in albumin was associated with a greater reduction in risk in patients aged ≥80 years vs. <80 years., Conclusions: In a large trial of acute HF, there were differences in baseline characteristics and outcomes amongst patients of different ages. Standard prognostic variables exhibit different utility in elderly patients., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Amino acids play a key role in multiple cellular processes. Amino acids availability is reduced in patients with heart failure (HF) with deleterious consequences on cardiac and whole-body metabolism. Several metabolic abnormalities have been identified in the failing heart, and many of them lead to an increased need of amino acids. Recently, several clinical trials have been conducted to demonstrate the benefits of amino acids supplementation in patients with HF. Although they have shown an improvement of exercise tolerance and, in some cases, of left ventricular function, they have many limitations, namely small sample size, differences in patients' characteristics and nutritional supplementations, and lack of data regarding outcomes. Moreover recent data suggest that a multi-nutritional approach, including also antioxidants, vitamins, and metals, may be more effective. Larger trials are needed to ascertain safety, efficacy, and impact on prognosis of such an approach in HF.

Acute heart failure (AHF) represents a major healthcare burden with a high risk of in-hospital and post-discharge mortality, which remained almost unchanged in the last few decades, underscoring the need of new treatments. Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone and has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. Recently, the new molecule serelaxin, a recombinant form of the naturally occurring hormone relaxin has been studied in patients hospitalized for AHF. In addition to vasodilation, serelaxin has anti-oxidative, anti-inflammatory and connective tissue regulating properties. In preclinical studies, it reduced both systemic and renal vascular resistance and, in the clinical trials Pre-RELAX-AHF and RELAX-AHF, it improved dyspnea and signs of congestion. In addition, serelaxin was associated with a reduction of 180-day mortality. The aim of this review is to summarize the pharmacological properties of serelaxin and the results of the preclinical and clinical studies.

Amino acids (AAs) availability is reduced in patients with heart failure (HF) leading to abnormalities in cardiac and skeletal muscle metabolism, and eventually to a reduction in functional capacity and quality of life. In this study, we investigate the effects of oral supplementation with essential and semi-essential AAs for three months in patients with stable chronic HF. The primary endpoints were the effects of AA's supplementation on exercise tolerance (evaluated by cardiopulmonary stress test and six minutes walking test (6MWT)), whether the secondary endpoints were change in quality of life (evaluated by Minnesota Living with Heart Failure Questionnaire-MLHFQ) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. We enrolled 13 patients with chronic stable HF on optimal therapy, symptomatic in New York Heart Association (NYHA) class II/III, with an ejection fraction (EF) <45%. The mean age was 59 ± 14 years, and 11 (84.6%) patients were male. After three months, peak VO2 (baseline 14.8 ± 3.9 mL/minute/kg vs follow-up 16.8 ± 5.1 mL/minute/kg; P = 0.008) and VO2 at anaerobic threshold improved significantly (baseline 9.0 ± 3.8 mL/minute/kg vs follow-up 12.4 ± 3.9 mL/minute/kg; P = 0.002), as the 6MWT distance (baseline 439.1 ± 64.3 m vs follow-up 474.2 ± 89.0 m; P = 0.006). However, the quality of life did not change significantly (baseline 21 ± 14 vs follow-up 25 ± 13; P = 0.321). A non-significant trend in the reduction of NT-proBNP levels was observed (baseline 1502 ± 1900 ng/L vs follow-up 1040 ± 1345 ng/L; P = 0.052). AAs treatment resulted safe and was well tolerated by all patients. In our study, AAs supplementation in patients with chronic HF improved exercise tolerance but did not change quality of life.

Background: Models to stratify risk for patients hospitalised for acute decompensated heart failure (ADHF) do not include the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels during hospitalisation., Objective: The aim of our study was to develop a simple yet robust discharge prognostication score including NT-proBNP for this notorious high-risk population., Design: Individual patient data meta-analyses of prospective cohort studies., Setting: Seven prospective cohorts with in total 1301 patients., Patients: Our study population was assembled from the seven studies by selecting those patients admitted because of clinically validated ADHF, discharged alive, and NT-proBNP measurements available at admission and at discharge., Main Outcome Measures: The endpoints studied were all-cause mortality and a composite of all-cause mortality and/or first readmission for cardiovascular reason within 180 days after discharge., Results: The model that incorporated NT-proBNP levels at discharge as well as the changes in NT-proBNP during hospitalisation in addition to age ≥75 years, peripheral oedema, systolic blood pressure ≤115 mm Hg, hyponatremia at admission, serum urea of ≥15 mmol/L and New York Heart Association (NYHA) class at discharge, yielded the best C-statistic (area under the curve, 0.78, 95% CI 0.74 to 0.82). The addition of NT-proBNP to a reference model significantly improved prediction of mortality as shown by the net reclassification improvement (62%, p<0.001). A simplified model was obtained from the final Cox regression model by assigning weights to individual risk markers proportional to their relative risks. The risk score we designed identified four clinically significant subgroups. The pattern of increasing event rates with increasing score was confirmed in the validation group (BOT-AcuteHF, n=325, p<0.001)., Conclusions: In patients hospitalised for ADHF, the addition of the discharge NT-proBNP values as well as the change in NT-proBNP to known risk markers, generates a relatively simple yet robust discharge risk score that importantly improves the prediction of adverse events.

The prevalence of heart failure (HF) increases with age. While clinical trials suggest that contemporary evidence-based HF therapies have reduced morbidity and mortality, these trials largely excluded the elderly. Questions remain regarding the clinical characteristics of elderly HF patients and the impact of contemporary therapies on their outcomes. This review presents the epidemiology of HF in the elderly and summarizes the data on the pathophysiology of the ageing heart. The clinical characteristics, treatment patterns, and outcomes of elderly HF patients are explored. Finally, the main gaps regarding HF therapies in the elderly and the opportunities for future trials are highlighted.

Several large-scale trials have demonstrated improved survival with the administration of ACE-inhibitors to patients with a recent myocardial infarction. Many ACE-inhibitors with different pharmacological properties have been shown to be safe and effective. More recently the data provided by the Survival of Myocardial Infarction Long-term Evaluation (SMILE) program indicate that zofenopril may favorably affect the prognosis of patients with a recent myocardial infarction and, according to the results of the SMILE-4 study, it may be superior to ramipril with respect to some variables (cardiovascular hospitalizations) when both these ACE-inhibitors are administered combined with acetylsalicylic acid.

Heart failure is the leading cause of death and hospitalization in industrialized countries and a major cause of healthcare costs. It is associated with severe symptoms and its prognosis remains poor. Further improvement is needed beyond the results of pharmacological treatment and devices. The role of nutrition has therefore been studied both in the early stages of heart failure, as a tool for the reduction of cardiovascular risk factors and in symptomatic heart failure, for the prevention and treatment of congestion and fluid overload. In addition, dietary supplements, such as n-3 polyunsaturated fatty acids and amino acids, may contribute to the improvement of prognosis and cardiac function, respectively. Finally, in advanced heart failure, nutrition may counteract the effects of muscle wasting and cardiac cachexia through an increase in caloric and protein intake and amino acid supplementation.

Aims: Myocardial injury during an episode of acute heart failure (AHF) may be important for patents' outcome. We hypothesised that an increase of cardiac troponin levels (cTnT) during hospitalisation, in patients with undetectable levels on admission (cTnT release), may be a more specific marker of myocardial damage. With this aim, we assessed the clinical and prognostic significance of high serum cTnT levels at the time of admission and that of cTnT release in 198 consecutive patients admitted for AHF and with no signs of acute coronary syndrome., Methods and Results: cTnT levels were serially measured at the time of admission, and after 6 and 12 h, in 198 consecutive patients admitted for AHF and with no signs of acute coronary syndrome. cTnT was detectable (>0.01 ng/mL) in 102 patients (52 %) and positive for myocardial necrosis (>0.03 ng/mL) in 78 patients (39 %). Negative cTnT at the time of admission became positive at 6 and/or 12 h in 36 (18 %) patients. Patients with increased cTnT levels were more likely to have coronary artery disease, hypertension, diabetes, and renal dysfunction. During a median follow-up duration of 247 days (IQR 96-480 days), the detection of increased cTnT levels was associated with a higher rate of all-cause deaths and, for cTnT release, all-cause death and cardiovascular rehospitalisation rate. CTnT release was an independent predictor of all-cause death and cardiovascular rehospitalisation, along with glomerular filtration rate, and the administration of inotropic agents during the initial hospitalisation., Conclusions: Increased cTnT levels are a frequent finding in patients with AHF. They are more likely to occur in patients with comorbidities and are associated with poorer outcomes. cTnT release is an independent predictor of poorer outcomes.

Opinion Statement: Interactions between the heart and kidney in the setting of acute heart failure are complex and have a substantial impact on patient care and outcomes. Further research is needed to better distinguish the different causes of kidney injury, allow its early and accurate prediction and detection, and identify therapeutic targets. Novel renal biomarkers could potentially provide a useful tool for this purpose. Restoration of optimal fluid status and resolution of renal venous congestion are important goals of therapy. Changes in serum creatinine, although an important marker of renal function, may not be associated with adverse outcomes, especially if they are transient and a consequence of more aggressive decongestion, or the appropriate titration of drugs affecting the renin-angiotensin-aldosterone axis. In addition to loop diuretics, a variety of drugs and strategies have been investigated in acute heart failure. Use of mineralocorticoid receptor antagonists and vasopressin antagonists may have potential benefits and should be further investigated. Inotropic agents should be limited in those clinical settings suggesting hypoperfusion. Ultrafiltration seems to provide a safe and effective tool to overcome diuretic resistance and optimize fluid status avoiding detrimental effects of diuretic therapy.

Background: Diabetes is associated with increased cardiovascular mortality. The aim of our study was to determine the prognostic factors for mortality in patients with type 2 diabetes (T2DM) and coronary artery disease (CAD) who underwent coronary angiography and percutaneous coronary intervention., Materials and Methods: Four hundred and forty-five consecutive T2DM patients with significant CAD (≥ 75% stenosis) were included in our analysis. All patients underwent standard clinical examination, laboratory tests and transthoracic echocardiography with measurement of the left ventricular ejection fraction. Severity of CAD at the coronary angiography was evaluated using the Gensini score. Clinical follow-up was completed at 1, 3 and 6 years., Results: During a mean follow-up of 73·3 ± 22·1 months, 109 patients died (24·5%). Significant determinants of an increased risk of death at multivariable analysis were age (p < 0·001), serum creatinine (p = 0·001), peripheral vascular disease (p = 0·002), serum glucose (p = 0·004), serum fibrinogen (p = 0·011) and history of heart failure (HF, p = 0·011). When all the variables were entered as categorical variables, with continuous variables split at their median value, only history of HF, estimated glomerular filtration rate, serum glucose, serum fibrinogen (all p < 0·0001) and beta-blocker therapy at discharge (p = 0·027) were selected., Conclusions: Our study shows a relatively good prognosis of patients with T2DM. Comorbidities, namely HF and renal impairment, are main determinants of survival., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Renal dysfunction is often present and/or worsens in patients with heart failure and this is associated with increased costs of care, complications and mortality. The cardiorenal syndrome can be defined as the presence or development of renal dysfunction in patients with heart failure. Its mechanisms are likely related to low cardiac output, increased venous congestion and renal venous pressure, neurohormonal and inflammatory activation and local changes, such as adenosine release. Many drugs, including loop diuretics, may contribute to worsening renal function through the activation of some of these mechanisms. Renal damage is conventionally defined by the increase in creatinine and blood urea nitrogen blood levels. However, these changes may be not related with renal injury or prognosis. New biomarkers of renal injury seem promising but still need to be validated. Thus, despite the epidemiological evidence, we are still lacking of satisfactory tools to assess renal injury and function and its prognostic significance.

Most patients with heart failure (HF) already have or develop renal dysfunction; this might contribute to their poor outcome. Current treatment for HF can also contribute to worsen renal function. High furosemide doses are traditionally associated with worsening renal function (WRF), but patients with fluid overload may benefit of aggressive fluid removal. Unfortunately, promising therapies like vasopressin antagonists and adenosine antagonists have not been demonstrated to improve outcomes. Likewise, correction of low renal blood flow through dopamine, inotropic agents, or vasodilators does not seem to be associated with a clear benefit. However, transient WRF associated with acute HF treatment may not necessarily portend a poor prognosis. In this review, we focus on the strategies to detect renal dysfunction in acute HF, the underlying pathophysiological mechanisms, and the potential treatments.

Background: Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients., Methods and Results: We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0-9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24-4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39-3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88-2.2 at multivariable analysis for mortality and rehospitalizations)., Conclusions: WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.

Introduction: Dyspnoea and peripheral oedema, caused by fluid redistribution to the lungs and/or by fluid overload, are the main causes of hospitalization in patients with heart failure and are associated with poor outcomes. Treatment of fluid overload should relieve symptoms and have a neutral or favorable effect on outcomes., Areas Covered: We first consider the results obtained with furosemide administration, which is still the mainstay of treatment of congestion in patients with heart failure. We then discuss important shortcomings of furosemide treatment, including the development of resistance and side effects (electrolyte abnormalities, neurohormonal activation, worsening renal function), as well as the relationship of furosemide - and its doses - with patient prognosis. Finally, the results obtained with potential alternatives to furosemide treatment, including different modalities of loop diuretic administration, combined diuretic therapy, dopamine, inotropic agents, ultrafiltration, natriuretic peptides, vasopressin and adenosine antagonists, are discussed., Expert Opinion: Relief of congestion is a major objective of heart failure treatment but therapy remains based on the administration of furosemide, an agent that is often not effective and is associated with poor outcomes. The results of the few controlled studies aimed at the assessment of new treatments to overcome resistance to furosemide and/or to protect the kidney from its untoward effects have been mostly neutral. Better treatment of congestion in heart failure remains a major unmet need.

Abnormalities of cardiac function, with high intraventricular filling pressure and low cardiac output, play a central role in patients with heart failure. Agents with inotropic properties are potentially useful to correct these abnormalities. However, with the exception of digoxin, no inotropic agent has been associated with favourable effects on outcomes. This is likely related to the mechanism of action of current agents, which is based on an increase in intracellular cyclic adenosine monophosphate and calcium concentrations. Novel agents acting through different mechanisms, such as sarcoplasmic reticulum calcium uptake, cardiac myosin and myocardial metabolism, have the potential to improve myocardial efficiency and lower myocardial oxygen consumption. These characteristics might allow a haemodynamic improvement in the absence of untoward effects on the clinical course and prognosis of the patients.

Hospitalizations for acute heart failure are associated with high mortality and readmission rates. Ten to 20% of the patients have signs of low cardiac output and fluid overload. The administration of inotropic agents to correct these hemodynamic abnormalities may be indicated in these patients. However, the risk to benefit ratio of inotropic agents is high and an increase of untoward effects and mortality has been suggested by many retrospective analyses and meta-analyses. Limitations of inotropic therapy seem mainly related to their mechanisms of action based, in the case of the traditional agents, on an increase in intracellular cyclic AMP and calcium concentrations. Concomitant peripheral vasodilation, such as in the case of the novel agent levosimendan is another important limitation, above when patients are hypotensive and/or treated with vasodilators and high doses of diuretics. Myosin activators, histaroxime, sarcoplasmic reticulum ATPase activators and metabolic agents seem promising as active through different mechanisms than traditional agents and, in many cases, not associated with tachycardia or hypotension. Further studies are, however, needed.

Objective: To evaluate the effects of a pill with drospirenone (3 mg) plus ethinyl E(2) (20 μg) (DRP/20EE) alone or associated with metformin or cyproterone acetate (CPA) on some metabolic cardiovascular risk factors in women with polycystic ovary syndrome (PCOS)., Design: Randomized, open-label clinical trial., Setting: Academic medical clinic., Patient(s): Forty-eight hirsute women with PCOS., Intervention(s): Patients were randomized to treatment with DRP/20EE or with DRP/20EE plus metformin (1,500 mg/d) or with DRP/20EE plus CPA (12.5 mg/d, 10 days per cycle) for 6 months., Main Outcome Measure(s): Blood pressure, lipid profile, and indexes of glucose tolerance and insulin sensitivity were assessed before and after 6 months of treatment., Result(s): Body mass index and blood pressure were not modified by any treatment. Treatment with DRP/EE20 did not change the lipid profile; DRP/EE20 plus metformin significantly increased high-density lipoprotein cholesterol concentrations; DRP/EE20 plus CPA significantly increased triglycerides and total cholesterol. The area under the curve for insulin was significantly decreased by DRP/EE20 and DRP/EE20 plus metformin, but it was significantly increased by DRP/EE20 plus CPA. Treatment with DRP/EE20 plus CPA significantly increased the homeostasis model assessment of insulin resistance index and significantly reduced the glucose to insulin ratio index. Treatment with DRP/EE20 significantly increased the glucose to insulin ratio index., Conclusion(s): Treatment with DRP/EE20 improved insulin sensitivity in hirsute women with PCOS, with no deterioration of lipid profile. This effect was not ameliorated by the addition of metformin. The positive metabolic effects of DRP are abolished by the concomitant use of CPA., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the metabolic profiles of adolescents with different phenotypes of polycystic ovary syndrome (PCOS)., Design: Observational study., Setting: University outpatient clinic., Patient(s): Adolescents with PCOS (n = 120) were divided into four groups: oligomenorrhea and hirsutism (O-H, n = 50), oligomenorrhea, hirsutism, and polycystic ovaries (PCO-O-H, n = 22), oligomenorrhea, hirsutism, and hyperandrogenemia (A-O-H, n = 28), oligomenorrhea, and hirsutism, hyperandrogenemia, and polycystic ovaries (PCO-A-O-H, n = 20). A control group of age-matched adolescents (n = 30) was included., Intervention(s): Subjects underwent physical and ultrasound evaluations; fasting blood samples were taken for the measurement of endocrine and metabolic parameters., Main Outcome Measure(s): The endocrine and metabolic profiles were evaluated., Result(s): Adolescents with PCOS showed reduced insulin sensitivity and dyslipidemia. Triglycerides, and total and low-density lipoprotein cholesterol were higher in the phenotypes with hyperandrogenemia. Insulin resistance and body mass index were not significantly different between PCOS phenotypes. Triglyceride positively and high-density lipoportein cholesterol levels negatively correlated with free testosterone and free androgen index., Conclusion(s): The risk of metabolic alterations may vary in adolescent PCOS patients with different phenotypes. Hyperandrogenemia is a risk factor for dyslipidemia. This information may be of relevance in counseling adolescents with PCOS.

Objective: The prevalence of the metabolic syndrome (MBS) abnormalities in Italian adolescents with polycystic ovary syndrome (PCOS) was evaluated., Design: Retrospective chart review., Setting: University outpatient clinic., Participants: Fifty-three adolescents with PCOS., Interventions: Subjects underwent a physical evaluation. Fasting blood samples were taken for the evaluation of metabolic parameters., Main Outcome Measures: The prevalence of MBS abnormalities according to de Ferranti criteria was assessed., Results: 9.4% of adolescents with PCOS had the MBS (three abnormalities). Twelve girls (22.7%) had two abnormalities. Seventeen (32.1%) of PCOS girls have no MBS abnormalities. PCOS adolescents with the MBS were more obese, insulin resistant and they had significantly higher levels of total and free testosterone. The number of metabolic abnormalities correlated with free, total testosterone, free androgen index (FAI) and body mass index (BMI). Groups with two or three abnormalities were not differentiated by BMI, insulin, lipids, blood pressure, but they were differentiated by total and free testosterone and FAI. Adolescents with the MBS have higher total and free testosterone and FAI than girls with two MBS abnormalities., Conclusions: The MBS and its components are present in some adolescents with PCOS, placing them at increased risk for cardiovascular disease early in adulthood. Hyperandrogenemia is a risk factor for MBS independent of obesity.

Objective: This study was performed to assess the microleakage of composite resin restorations bonded in Er:YAG laser-prepared cavities using a semi-direct technique, in comparison with diamond bur-prepared cavities., Background Data: Previous in vitro studies assessed the performance of total-etch and self-etch adhesive systems by investigating the microleakage of direct composite resin restorations., Materials and Methods: Class V cavities were randomly prepared in buccal and lingual surfaces of 20 human molars using a diamond bur and an Er:YAG laser (fluence 50 J/cm2). Composite resin inlays were bonded using a self-curing adhesive system and a composite resin luting cement. Microleakage was assessed using a methylene blue dye penetration method. The length of dye penetration along the occlusal margin, the length of dye penetration along the cervical margin, and the total length of the interface were recorded in millimeters. The total length of infiltration and the ratio of infiltration were then calculated., Results: The ratio of dye infiltration was 0.20 +/- 0.22 for bur-prepared cavities and 0.27 +/- 0.30 for Er:YAG laser-prepared cavities, with no significant difference (Wilcoxon test, p = 0.77)., Conclusion: In terms of microleakage, our results supported the use of the Er:YAG laser to remove carious tissues and prepare cavities in clinical practice.

Purpose: This study was conducted to evaluate body weight and composition during oral contraception with 30 microg ethinylestradiol plus 3 mg drospirenone (30EE+DRSP) in women affected by premenstrual syndrome (PMS) with somatic symptoms related to water retention., Design: This prospective study was performed using multifrequency bioelectrical impedance analysis in 18 normally cycling PMS patients (mean age, 28.8 years) evaluated at baseline, during the luteal phase of the menstrual cycle and after 3 and 6 cycles of 30EE+DRSP. Total body water (TBW), intracellular water (ICW), extracellular water (ECW), fat mass and fat-free mass were evaluated. Body weight, waist-to-hip ratio and blood pressure were also determined at each visit. Basal values were compared with those measured in 31 healthy females without PMS (controls)., Results: PMS patients have higher levels of TBW and ICW than controls. After 6 months of 30EE+DRSP, TBW and ECW were significantly lower than before treatment. No significant variations in ICW or in the other parameters were observed., Conclusion: In women with PMS, 30EE+DRSP reduces the concentrations in TBW and ECW. This effect is likely due to the antimineralocorticoid activity of DRSP. Whether these changes may account for the improvement of premenstrual fluid-related symptoms reported with this formulation is discussed.

Purpose: This nonrandomized study aimed to evaluate body weight and composition during the menstrual cycle and during oral contraception with 30 microg of ethinylestradiol plus 3 mg of drospirenone (EE+DRSP)., Design: Multifrequency bioelectrical impedance analysis was carried out in 38 normally cycling women (mean age, 25.5 years) at baseline during the follicular phase (FP) and the luteal phase (LP) of the menstrual cycle and after three and six cycles of EE+DRSP to evaluate total body water (TBW), intracellular water (ICW), extracellular water (ECW), fat mass and fat-free mass. Body weight, waist-to-hip ratio, blood pressure and the plasma concentrations of electrolytes were also determined at each visit., Results: TBW and ECW increased in the LP. During EE+DRSP, TBW and ECW were significantly lower than in the LP but similar to the values measured in the FP. No significant variations in ICW or in the other parameters were observed., Conclusion: EE+DRSP maintains the same concentrations in TBW and ECW observed in the FP. This effect is likely due to the antimineralocorticoid activity of DRSP, which counteracts the water retention elicited by estrogen.

Context: An altered lipid profile is common in polycystic ovary syndrome (PCOS) and is usually characterized by increased triglycerides and low high-density lipoprotein (HDL)-cholesterol levels. In the general population, these alterations are often associated with the increase of small low-density lipoproteins (LDLs) in the so-called "atherogenic lipoprotein phenotype" (ALP) that determines a further increase of cardiovascular risk. In this study, we evaluated the presence of ALP in the plasma of women with PCOS., Setting: Measurements and analysis of LDL size were performed at the Clinic of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital, Zurich. PCOS patients were recruited at the Department of Clinical Medicine, University of Palermo, and the Department of Obstetrics and Gynecology, University of Pisa., Patients: Thirty patients with PCOS (hyperandrogenism and chronic anovulation) and 24 matched controls were studied. Anthropometric data, blood glucose, serum insulin lipid profile, and LDL size and subclasses were evaluated., Results: Compared with controls, patients with PCOS had higher plasma concentrations of insulin and triglycerides and lower HDL-cholesterol concentrations but no differences in LDL-cholesterol and total cholesterol. Patients with PCOS had smaller LDL size due to a reduction in LDL subclass I, with a concomitant increase in LDL subclasses III and IV. Fourteen PCOS patients had an increase of smaller LDL particles, and it represented the second most common lipid alteration after decrease in HDL-cholesterol. However, because in this PCOS population hypertriglyceridemia was only present in two patients, complete ALP was relatively uncommon., Conclusions: Increase of type III or type IV LDL subclasses is a common finding in PCOS and represents the second most common lipid alteration after HDL-cholesterol decrease. However, in our PCOS patients, because of relatively low triglyceride levels, complete ALP is uncommon.

Objectives: To evaluate the pattern of mineral density in eumenorrhoic and oligomenorrhoic perimenopausal women, and assess the effects of different low dose oral contraceptives (OC) on bone metabolism and spine bone density., Methods: Spine bone density was evaluated in a longitudinal 2-year follow-up, randomized, unblinded, uncontrolled clinical trial conducted in healthy, normally menstruating perimenopausal women, perimenopausal oligomenorrhoic women and in perimenopausal oligomenorrhoic women treated with an oral contraceptive containing 20 microg ethinyl estradiol plus 0.15 mg desogestrel, 0.100 mg levonorgestrel, 0.75 mg of gestodene (n=15 in each group). The results were analyzed by factorial or repeated measures analysis of variance, as appropriate., Results: During the observation period, in normal menstruating women there were no changes in menstrual cycle, plasma FSH and estradiol levels, and spine bone density. In oligomenorrhoic untreated women an increase in cycle length, with a concomitant decrease in plasma estradiol and an increase in plasma FSH levels were evidenced (p<0.05). In this group a significant decrease in bone density (p<0.05) occurred. In OC-treated women, a significant (p<0.05) increase in bone density was observed, with no differences among different groups., Conclusion: Different progestins used in OC preparations do not modify the bone sparing effect of perimenopausal OC administration avoiding the decrease in bone density.