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Background and aims It is unknown whether the prognostic role of diabetes (T2DM) in outpatients with chronic heart failure (CHF) is independent of the most important echocardiographic markers of poor prognosis. The aims of this analysis were to evaluate whether T2DM modifies the risk of mortality in CHF patients stratified by etiology of disease or by right-ventricular to pulmonary arterial coupling at echocardiography and to evaluate how T2DM interacts with the prognostic role of cardiac plasma biomarkers. Methods and results This is a retrospective analysis of 1627 CHF outpatients who underwent a complete echocardiographic examination. During a median follow-up period of 63 months 255 patients died. Poor right-ventricular to pulmonary arterial coupling and reduced left ventricular ejection fraction were independent predictors of outcome, whereas ischemic etiology and T2DM were not. T2DM interacted with etiology increasing the risk of mortality by 32% among patients with ischemic disease (p = 0.003). Elevated hsTNI plasma levels were associated with poor survival in T2DM but not in non-diabetic patients. Conclusion T2DM signals a worse outcome in ischemic CHF patients regardless of the echocardiographic phenotype. High plasma levels of hsTNI are stronger predictors of mortality in CHF patients with T2DM than in patients without diabetes.

Background: It is uncertain whether exposure to renin–angiotensin system (RAS) modifiers affects the severity of the new coronavirus disease 2019 (COVID-19) because most of the available studies are retrospective. Methods: We tested the prognostic value of exposure to RAS modifiers (either angiotensin-converting enzyme inhibitors [ACE-Is] or angiotensin receptor blockers [ARBs]) in a prospective study of hypertensive patients with COVID-19. We analyzed data from 566 patients (mean age 75 years, 54% males, 162 ACE-Is users, and 147 ARBs users) hospitalized in five Italian hospitals. The study used systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the primary outcome. Results: Sixty-six patients died during hospitalization. Exposure to RAS modifiers was associated with a significant reduction in the risk of in-hospital mortality when compared to other BP-lowering strategies (odds ratio [OR]: 0.54, 95% confidence interval [CI]: 0.32 to 0.90, p = 0.019). Exposure to ACE-Is was not significantly associated with a reduced risk of in-hospital mortality when compared with patients not treated with RAS modifiers (OR: 0.66, 95% CI: 0.36 to 1.20, p = 0.172). Conversely, ARBs users showed a 59% lower risk of death (OR: 0.41, 95% CI: 0.20 to 0.84, p = 0.016) even after allowance for several prognostic markers, including age, oxygen saturation, occurrence of severe hypotension during hospitalization, and lymphocyte count (adjusted OR: 0.37, 95% CI: 0.17 to 0.80, p = 0.012). The discontinuation of RAS modifiers during hospitalization did not exert a significant effect (p = 0.515). Conclusions: This prospective study indicates that exposure to ARBs reduces mortality in hospitalized patients with COVID-19.

Resumo Justificativa e objetivos A ecocardiografia transtoracica pode ser potencialmente util para obter uma estimativa rapida, precisa e nao invasiva do debito cardiaco. Avaliamos se os intensivistas nao cardiologistas podem obter uma determinacao precisa e reprodutivel do debito cardiaco em pacientes mecanicamente ventilados e hemodinamicamente instaveis. Metodos Avaliamos 25 pacientes em unidade de terapia intensiva, mecanicamente ventilados, hemodinamicamente instaveis, com cateteres de arteria pulmonar posicionados. O debito cardiaco foi calculado com a tecnica de ecocardiografia transtoracica com Doppler pulsatil aplicada a via de saida do ventriculo esquerdo no corte apical (5‐câmaras) por dois medicos intensivistas que receberam treinamento basico em ecocardiografia transtoracica e treinamento especifico focado em Doppler, via de saida do ventriculo esquerdo e determinacao da integral de tempo‐velocidade. Resultados A avaliacao do debito cardiaco pelo ecocardiograma transtoracico foi factivel em 20 dos 25 pacientes inscritos (80%) e mostrou excelente reprodutibilidade entre operadores (teste de correlacao de Pearson r = 0,987; K de Cohen = 0,840). No geral, o vies medio foi de 0,03 L.min−1, com limites de concordância de ‐0,52 e +0,57 L.min−1. O coeficiente de correlacao de concordância (ρc) foi 0,986 (95% IC 0,966‐0,995) e 0,995 (95% IC 0,986‐0,998) para os medicos 1 e 2, respectivamente. O valor de precisao (Cb) da mensuracao de COTTE foi de 0,999 para ambos os observadores. O valor de precisao (ρ) da mensuracao de COTTE foi de 0,986 e 0,995 para os observadores 1 e 2, respectivamente. Conclusoes Um treinamento especifico focado na determinacao do Doppler e VTI, adicionado ao treinamento padrao em ecocardiografia transtoracica basica, permitiu que medicos nao cardiologistas da unidade de terapia intensiva obtivessem uma avaliacao rapida, reprodutivel e precisa do debito cardiaco instantâneo na maioria dos pacientes mecanicamente ventilados em unidade de terapia intensiva.

We perform a theoretical and computational study of the classical linearisation techniques (LT) and we propose a new LT for binary quadratic problems (BQPs). We discuss the relations between the linear programming (LP) relaxations of the considered LT for generic BQPs. We prove that for a specific class of BQP all the LTs have the same LP relaxation value. We also compare the LT computational performance for four different BQPs from the literature. We consider the Unconstrained BQP and the maximum cut of edge-weighted graphs and, in order to measure the effects of constraints on the computational performance, we also consider the quadratic extension of two classical combinatorial optimization problems, i.e., the knapsack and stable set problems.

Aims heart failure (HF) and coronary artery disease (CAD) are independent predictors of death in patients with COVID-19. The adverse prognostic impact of the combination of HF and CAD in these patients is unclear. Methods and results we analysed data from 954 consecutive patients hospitalized for SARS-CoV-2 in five Italian Hospitals from February 23 to May 22, 2020. The study was a systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the outcome measure. Mean duration of hospitalization was 33 days. Mortality was 11% in the total population and 7.4% in the group without evidence of HF or CAD (reference group). Mortality was 11.6% in the group with CAD and without HF (odds ratio [OR]: 1.6, p = 0.120), 15.5% in the group with HF and without CAD (OR: 2.3, p = 0.032), and 35.6% in the group with CAD and HF (OR: 6.9, p, Graphical abstract Image, graphical abstract

The implantable cardioverter-defibrillator (ICD) is the mainstay therapy for primary prevention of sudden cardiac death in patients with heart failure with a reduced ejection fraction. Current indications for prophylactic ICD are based on the results of randomized controlled trials dating back to 15-20 years ago, which have usually enrolled highly selected patients with few comorbidities and only a small number of patients aged >75 years. Existing literature suggest an age-dependent attenuation of the efficacy of the ICD. Because of the ageing of the population, there is need for data addressing device efficacy among older patients that also considers the impact of geriatric syndromes on health status. The assessment of frailty may be of value in identifying elderly patients who may or may not benefit from ICD placement for primary prevention of sudden cardiac death.

Divide and conquer, from Latin divide et impera, is one of the key techniques for tackling combinatorial optimization problems. It relies on the idea of decomposing complex problems into a sequence of subproblems that are then easier to handle. Decomposition techniques (such as Dantzig-Wolfe, Lagrangian, or Benders decomposition) are extremely effective in a wide range of applications, including cutting and packing, production and scheduling, routing and logistics, telecommunications, transportation, and many others. Moreover, decomposition techniques play an important role in many different fields of mixed-integer linear and non-linear optimization, multi objective optimization, optimization under uncertainty, bilevel optimization, etc. Despite the tremendous amount of research on these topics, the mathematical optimization community is constantly faced with new challenges coming from theoretical aspects and real world applications that require the development of new advanced tools.

Aims The most recent European guidelines have proposed new definitions of pulmonary hypertension (PH) in left heart disease, to better approach the characteristics required to reflect the presence of pulmonary vascular disease. The purpose of this study was to assess whether different haemodynamic definitions of post-capillary PH imply a different reversibility of PH in response to acute vasodilator administration in heart failure patients with reduced ejection fraction and PH (HFrEF-PH). Methods and results Right heart catheterization and reversibility testing was performed in 156 HFrEF-PH patients. Patients were classified as combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH) vs. isolated post-capillary pulmonary hypertension (Ipc-PH) and on the basis of diastolic pulmonary gradient (DPG) ≥ 7 vs. 12 vs. ≤12 mmHg. After vasodilator administration, Cpc-PH patients showed a greater per cent improvement in pulmonary vascular resistance (PVR), DPG and TPG as compared with Ipc-PH patients (all Pint 12 mmHg groups (28.3, 26.7 and 18.9%, respectively). Conclusion Although substantial improvements in PVR, DPG and TPG were observed in Cpc-PH patients after acute vasodilator administration, this response was associated with persistent abnormalities in the PVR vs. PCa relationship. The link between baseline right heart haemodynamics and pulmonary vascular disease remains elusive.

Aims To evaluate whether the clinical and echocardiographic correlates and the prognostic significance of right ventricular (RV) dysfunction are different in heart failure patients with reduced (HFrEF), mid-range (HFmrEF), or preserved (HFpEF) left ventricular ejection fraction. Methods and results The study included 1663 patients with heart failure caused by ischaemic or hypertensive heart disease or by idiopathic cardiomyopathy. Left ventricular ejection fraction was 40 mmHg was by far the strongest correlate of a reduced TAPSE in HFpEF and HFmrEF patients (interaction analysis, P = 0.0011). TAPSE/PASP proved to be a powerful predictor of prognosis in all patients. Conclusions The correlates of RV dysfunction differ in HFrEF compared with HFpEF and HFmrEF patients. Regardless of the extent of LV dysfunction, the TAPSE/PASP ratio is a powerful independent predictor of prognosis in all heart failure patients.

Despite improvements in treatments, the prognosis of heart failure remains poor. Elderly patients with heart failure are burdened with multiple co-morbidities and polypharmacy. Multidisciplinary disease-management programs are recommended as standard care for patients at high risk of hospitalization. Cardiac rehabilitation is defined a coordinated multidimensional intervention that integrates the basic elements in multidisciplinary management programs with a continuing program of physical activity and exercise training. Cardiac rehabilitation services can be provided on an inpatient or outpatient basis according to the clinical characteristics and severity of the disease. Data support the usefulness of inpatient cardiac rehabilitation interventions soon after hospitalization for acute decompensated heart failure as a “transition care service” to overcome the particularly high risk “vulnerable” phase. Although in the elderly, physical activity is conditioned by the general clinical conditions, the presence of comorbidities and frailty, several data underscore the importance of improving exercise capacity in the elderly vulnerable patient.

Because of the demographic shift and the increased proportion of patients surviving acute critical illnesses, the number of people living with severely disabling chronic diseases and, consequently, the demand for rehabilitation are expected to increase sharply overtime. As underscored by theWorld Health Organization (WHO), there is substantial evidence that the provision of inpatient rehabilitation in specialized rehabilitation units to people with complex needs is effective in fostering functional recovery, improving health-related quality of life, increasing independence, reducing institutionalization rate, and improving prognosis. Recent studies in the real-world setting reinforce the evidence that patients with ischemic heart disease or stroke benefit from rehabilitation in terms of improved prognosis. In addition, there is evidence of the effectiveness of rehabilitation for the prevention of functional deterioration in patients with complex and/or severe chronic diseases. Given this evidence of effectiveness, rehabilitation should be regarded as an essential part of the continuum of care (transitional care). Nonetheless, rehabilitation still is underdeveloped and underused. A new model based on ICD and ICF WHO disease and disfunctioning classification respectively and on pre-set clinical pathways is described. The aim of this model is to optimize clinical care in times of shortage of resources and huge increase in older chronic multi morbid patients.A causa dell’invecchiamento della popolazione globale e dell’aumentato numero di pazienti che sopravvivono ad eventi acuti con disabilità, il numero di persone con malattie croniche e la domanda di cure riabilitative di qualità aumenteranno vertiginosamente nel tempo. Come sottolineato dalla Organizzazione Mondiale della Sanità (OMS) c’è una forte evidenza che sottoporre pazienti con bisogni complessi a riabilitazione in regime di ricovero in Unità Specializzate di Medicina Riabilitativa porta a recupero funzionale, miglioramento della qualità della vita in relazione allo stato di salute e aumento della indipendenza della persona, riducendo così il ricorso a strutture di ricovero lungodegenziale e migliorandone la prognosi. Recenti studi rinforzano l’evidenza che pazienti con cardiopatia ischemica o ictus beneficino della medicina specialistica e riabilitativa in termini di prognosi. Vi è inoltre evidenza dell’efficacia della riabilitazione in termini di prevenzione del deterioramento funzionale nelle malattie croniche severe e complesse. In quest’ottica la riabilitazione deve essere intesa come parte essenziale nel continuum delle cure in occasione di eventi acuti. Nonostante queste premesse la medicina riabilitativa è ancora sottoutilizzata e non pienamente studiata. Un nuovo modello basato sulle classificazioni ICD e ICF dell’OMS rispettivamente per codici di malattie e di disfunzione (intesa nel senso più ampio) e su percorsi di diagnosi e cura strutturati informaticamente è stato sviluppato con lo scopo di ottimizzare qualità e quantità di cure in tempi di scarsità di risorse e aumento di pazienti cronici e complessi.

Due to epidemiological and social changes related to the increase in the average life expectancy, hospital users are characterized by elderly chronic and comorbid patients who require recurrent hospitalizations often with disability outcomes. In this framework, an innovative clinical and management hospitalization model is the adequate answer to systematically promote the patient independence. Main features are interdisciplinary and integrated care pathways facing both disease and disability biologically and functionally diagnosed by ICD and ICF. The definition, personalization of pathways/protocols and outcome evaluation represent the foundations of this new model for patient care. The digitalization of hospital clinical data and medical knowledge make the model feasible and fitting the recent WHO guideline: recommendations on digital interventions for health system strengthening.A causa dei cambiamenti epidemiologici e della società legati all’aumento della aspettativa di vita i pazienti che afferiscono in ospedale sono generalmente più anziani, cronici e comorbidi e richiedono frequenti re-ospedalizzazioni spesso con esiti disabilitanti. In questo contesto un nuovo modello di ospedalizzazione innovativo sia dal punto di vista clinico che di management sembra essere la risposta adeguata per promuovere sistematicamente l’autonomia del paziente. Caratteristiche principali del modello sono l’interdisciplinarietà e percorsi di cura integrati che affrontino la malattia e la disabilità valutate con le classificazioni ICD e ICF. Le basi fondanti di questo nuovo modello di cura sono la definizione e la personalizzazione dei percorsi diagnostico terapeutici assistenziali (PDTA). La digitalizzazione dei dati clinici ospedalieri ricavati dai percorsi/protocolli rendono fattibile il modello e si allineano con le recenti line guida dell’OMS sulla digitalizzazione degli interventi nel rafforzare i sistemi sanitari.

Background and objectives: Transthoracic echocardiography may potentially be useful to obtain a prompt, accurate and non-invasive estimation of cardiac output. We evaluated whether non-cardiologist intensivists may obtain accurate and reproducible cardiac output determination in hemodynamically unstable mechanically ventilated patients. Methods: We studied 25 hemodynamically unstable mechanically ventilated intensive care unit patients with a pulmonary artery catheter in place. Cardiac output was calculated using the pulsed Doppler transthoracic echocardiography technique applied to the left ventricular outflow tract in apical 5 chamber view by two intensive care unit physicians who had received a basic Transthoracic Echocardiography training plus a specific training focused on Doppler, left ventricular outflow tract and velocity-time integral determination. Results: Cardiac output assessment by transthoracic echocardiography was feasible in 20 out of 25 enrolled patients (80%) and showed an excellent inter-operator reproducibility (Pearson correlation test r = 0.987; Cohen's K = 0.840). Overall, the mean bias was 0.03 L.min−1, with limits of agreement −0.52 and +0.57 L.min−1. The concordance correlation coefficient (ρc) was 0.986 (95% IC 0.966–0.995) and 0.995 (95% IC 0.986–0.998) for physician 1 and 2, respectively. The value of accuracy (Cb) of COTTE measurement was 0.999 for both observers. The value of precision (ρ) of COTTE measurement was 0.986 and 0.995 for observer 1 and 2, respectively. Conclusions: A specific training focused on Doppler and VTI determination added to the standard basic transthoracic echocardiography training allowed non-cardiologist intensive care unit physicians to achieve a quick, reproducible and accurate snapshot cardiac output assessment in the majority of mechanically ventilated intensive care unit patients. Resumo: Justificativa e objetivos: A ecocardiografia transtorácica pode ser potencialmente útil para obter uma estimativa rápida, precisa e não invasiva do débito cardíaco. Avaliamos se os intensivistas não cardiologistas podem obter uma determinação precisa e reprodutível do débito cardíaco em pacientes mecanicamente ventilados e hemodinamicamente instáveis. Métodos: Avaliamos 25 pacientes em unidade de terapia intensiva, mecanicamente ventilados, hemodinamicamente instáveis, com cateteres de artéria pulmonar posicionados. O débito cardíaco foi calculado usando a técnica de ecocardiografia transtorácica com Doppler pulsátil aplicada à via de saída do ventrículo esquerdo no corte apical (5-câmaras) por dois médicos intensivistas que receberam treinamento básico em ecocardiografia transtorácica e treinamento específico focado em Doppler, via de saída do ventrículo esquerdo e determinação da integral de tempo-velocidade. Resultados: A avaliação do débito cardíaco pelo ecocardiograma transtorácico foi factível em 20 dos 25 pacientes inscritos (80%) e mostrou excelente reprodutibilidade entre operadores (teste de correlação de Pearson r = 0,987; K de Cohen = 0,840). No geral, o viés médio foi de 0,03 L.min−1, com limites de concordância de −0,52 e +0,57 L.min−1. O coeficiente de correlação de concordância (ρc) foi 0,986 (95% IC 0,966–0,995) e 0,995 (95% IC 0,986–0,998) para os médicos 1 e 2, respectivamente. O valor de precisão (Cb) da mensuração de COTTE foi de 0,999 para ambos os observadores. O valor de precisão (ρ) da mensuração de COTTE foi de 0,986 e 0,995 para os observadores 1 e 2, respectivamente. Conclusões: Um treinamento específico focado na determinação do Doppler e VTI, adicionado ao treinamento padrão em ecocardiografia transtorácica básica, permitiu que médicos não cardiologistas da unidade de terapia intensiva obtivessem uma avaliação rápida, reprodutível e precisa do débito cardíaco instantâneo na maioria dos pacientes mecanicamente ventilados em unidade de terapia intensiva. Keywords: Cardiac output, Transthoracic echocardiography, Pulmonary artery catheter, Intensive Care Unit, Palavras-chave: Débito cardíaco, Ecocardiografia transtorácica, Cateter de artéria pulmonar, Unidade de Terapia Intensiva

Digoxin use remains a common therapeutic option in the pharmacological control of heart rate in patients with atrial fibrillation, endorsed in current guidelines with the same level of evidence than beta-blockers in patients with and without heart failure. Digoxin has a narrow therapeutic range and is influenced by drug‐to‐drug interactions, serum electrolyte concentrations, and renal function. Conflicting data exist regarding adverse outcomes that are associated with digoxin use in patients with atrial fibrillation. It remains unclear whether the association between digoxin use and worse clinical outcome is causal or may be the result of confounding by differences in the characteristics of patents including age, comorbidities and treatment. Particularly in older patients with atrial fibrillation, who are frequently prescribed a multitude of agents for stroke prevention, treatment of cardiovascular disease and other comorbidities, use of digoxin should be cautious and instituted with assessment of drug concentrations.

We investigate the computational potential of split inequalities for non-convex quadratic integer programming, first introduced by Letchford (2010) and further examined by Burer and Letchford (2012). These inequalities can be separated by solving convex quadratic integer minimization problems. For small instances with box-constraints, we show that the resulting dual bounds are very tight; they can close a large percentage of the gap left open by both the RLT- and the SDP-relaxations of the problem. The gap can be further decreased by separating the so-called non-standard split inequalities, which we examine in the case of ternary variables.

The most recent European guidelines have proposed new definitions of pulmonary hypertension (PH) in left heart disease, to better approach the characteristics required to reflect the presence of pulmonary vascular disease. The purpose of this study was to assess whether different haemodynamic definitions of post-capillary PH imply a different reversibility of PH in response to acute vasodilator administration in heart failure patients with reduced ejection fraction and PH (HFrEF-PH).Right heart catheterization and reversibility testing was performed in 156 HFrEF-PH patients. Patients were classified as combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH) vs. isolated post-capillary pulmonary hypertension (Ipc-PH) and on the basis of diastolic pulmonary gradient (DPG) ≥ 7 vs.7 mmHg or of transpulmonary gradient (TPG)12 vs. ≤12 mmHg. After vasodilator administration, Cpc-PH patients showed a greater per cent improvement in pulmonary vascular resistance (PVR), DPG and TPG as compared with Ipc-PH patients (all PAlthough substantial improvements in PVR, DPG and TPG were observed in Cpc-PH patients after acute vasodilator administration, this response was associated with persistent abnormalities in the PVR vs. PCa relationship. The link between baseline right heart haemodynamics and pulmonary vascular disease remains elusive.

Objective The severity of central sleep apnoea (CSA), a common comorbidity in patients with chronic heart failure (CHF) and reduced ejection fraction, markedly decreases from the supine to the lateral sleeping position, with no difference between the left and right positions. The mechanisms responsible for this beneficial effect have not yet been elucidated. Methods We tested the hypothesis that CSA attenuation in the left lateral position is due, at least in part, to an improvement in cardiac haemodynamics. Sixteen CHF patients (male, aged 60 ± 7 years, New York Heart Association class 2.6 ± 0.5, left ventricular ejection fraction [LVEF] 30% ± 5%) with moderate-to-severe CSA underwent two consecutive tissue Doppler echocardiography examinations in random order, one in the left lateral position (90°) and the other in the supine position (0°). The following parameters were obtained: left ventricular end-diastolic volume (LVEDV) and LVEF, left atrial volume (LAV) and right atrial volume (RAV), mitral regurgitation (MR), cardiac output (CO), transmitral protodiastolic (E) wave deceleration time (DT), E/e′ ratio, tricuspid annular plane systolic excursion (TAPSE), and right ventricular−atrial gradient (RVAG). Results The LAV, MR, E/e′, RAV, and RVAG significantly increased, whereas the LVEF and TAPSE significantly decreased in the left lateral position. All changes, however, were of negligible clinical significance. No significant changes were observed in CO, DT, and LVEDV. Conclusions This study shows that the reduction of CSA severity from the supine to the left lateral position in patients with CHF is not due to an improvement in cardiac haemodynamics. Other, noncardiac factors are likely to represent the main cause.

Nutritional status (NS) is not routinely assessed in HF. We sought to evaluate whether NS may be additive to a comprehensive pre-discharge evaluation based on a clinical score that includes BMI (MAGGIC) and on an index of functional capacity (six minute walking test, 6mWT) in HF patients.The CONUT (Controlling Nutritional Status) score (including serum albumin level, total cholesterol and lymphocyte count) was computed in 466 consecutive patients (mean age 61 ± 11 years, NYHA class 2.6 ± 0.6, LVEF 34 ± 11%, BMI 27.2 ± 4.5) who had pre-discharge MAGGIC and 6MWT. The endpoint was all-cause mortality. Mild or moderate undernourishment was present in 54% of patients with no differences across BMI strata. The 12-month event rate was 7.7%. Deceased patients had a more compromised NS (CONUT 2.8 ± 1.5 vs 1.7 ± 1.3, p 0.0001), and a more advanced HF (MAGGIC 28.2 ± 6.0 vs 22.0 ± 6.6, p 0.0001; 6MWT 311.1 ± 102.2 vs. 408.9 ± 95.9 m, p 0.0001). The 12-month mortality rate varied from 4% for well-nourished to 11% for undernourished patients (p = 0.008). At univariate analysis, the CONUT was predictive for all-cause mortality with a Hazard Ratio of 1.701 [95% CI 1.363-2.122], p 0.0001. Multivariable analysis showed that the CONUT significantly added to the combination of MAGGIC and 6MWT and improved predictive discrimination and risk classification (c-index 0.82 [95% CI 0.75-0.88], integrated discrimination improvement 0.028 [95% CI 0.015-0.081]).In HF patients assessment of NS, significantly improves prediction of 12-month mortality on top of the information provided by clinical evaluation and functional capacity and should be incorporated in the overall assessment of HF patients.

RE-START is a multicenter, randomized, prospective, open, controlled trial aiming to evaluate the feasibility and the short- and medium-term effects of an earlystart AET program on functional capacity, symptoms and neurohormonal activation in chronic heart failure (CHF) patients with recent acute hemodynamic decompensation. Study endpoints will be: 1) safety of and compliance to AET; 2) effects of AET on i) functional capacity, ii) patient- reported symptoms and iii) AET-induced changes in beta-adrenergic receptor signaling and circulating angiogenetic and inflammatory markers. Two-hundred patients, randomized 1:1 to training (TR) or control (C), will be enrolled. Inclusion criteria: 1) history of systolic CHF for at least 6 months, with ongoing acute decompensation with need of intravenous diuretic and/or vasodilator therapy; 2) proBNP >1000 pg/ml at admission. Exclusion criteria: 1) ongoing cardiogenic shock; 2) need of intravenous inotropic therapy; 3) creatinine >2.5 mg/dl at admission. After a 72-hour run-in period, TR will undergo the following 12-day early-start AET protocol: days 1-2: active/passive mobilization (2 sessions/day, each 30 minutes duration); days 3-4: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 5-10 minutes duration); days 5-8: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 15-20 minutes duration); days 9-12: as days 1-2 + bedside cycle ergometer at 10-20 W (3 sessions/day, each 15-20 minutes duration). During the same period, C will undergo the same activity protocol as in days 1-2 for TR. All patients will undergo a 6- minWT at day 1, 6, 12 and 30 and echocardiogram, patient- reported symptoms on 7-point Likert scale and measurement of lymphocyte G protein coupled receptor kinase, VEGF, angiopoietin, TNF alfa, IL-1, IL-6 and eNOS levels at day 1, 12 and 30.

RE-START is a multicenter, randomized, prospective, open, controlled trial aiming to evaluate the feasibility and the short- and medium-term effects of an early-start AET program on functional capacity, symptoms and neurohormonal activation in chronic heart failure (CHF) patients with recent acute hemodynamic decompensation. Study endpoints will be: 1) safety of and compliance to AET; 2) effects of AET on i) functional capacity, ii) patient-reported symptoms and iii) AET-induced changes in beta-adrenergic receptor signaling and circulating angiogenetic and inflammatory markers. Two-hundred patients, randomized 1:1 to training (TR) or control (C), will be enrolled. Inclusion criteria: 1) history of systolic CHF for at least 6 months, with ongoing acute decompensation with need of intravenous diuretic and/or vasodilator therapy; 2) proBNP1000 pg/mI at admission. Exclusion criteria: 1) ongoing cardiogenic shock; 2) need of intravenous inotropic therapy; 3) creatinine2.5 mg/dl at admission. After a 72-hour run-in period, TR will undergo the following 12-day early-start AET protocol: days 1-2: active/passive mobilization (2 sessions/day, each 30 minutes duration); days 3-4: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 5-10 minutes duration); days 5-8: as days 1-2 + unloaded bedside cycle ergometer (3 sessions/day, each 15-20 minutes duration); days 9-12: as days 1-2 + bedside cycle ergometer at 10-20 W (3 sessions/day, each 15-20 minutes duration). During the same period, C will undergo the same activity protocol as in days 1-2 for TR. All patients will undergo a 6-min WT at day 1, 6, 12 and 30 and echocardiogram, patient-reported symptoms on 7-point Likert scale and measurement of lymphocyte G protein coupled receptor kinase, VEGF, angiopoietin, TNF alfa, IL-1, IL-6 and eNOS levels at day 1, 12 and 30.

Background— The predictive value of heart rate variability (HRV) in chronic heart failure (CHF) has never been tested in a comprehensive multivariate model using short-term laboratory recordings designed to avoid the confounding effects of respiration and behavioral factors. Methods and Results— A multivariate survival model for the identification of sudden (presumably arrhythmic) death was developed with data from 202 consecutive patients referred between 1991 and 1995 with moderate to severe CHF (age 52±9 years, left ventricular ejection fraction 24±7%, New York Heart Association class 2.3±0.7; the derivation sample). Time- and frequency-domain HRV parameters obtained from an 8′ recording of ECG at baseline and during controlled breathing (12 to 15 breaths/min) were challenged against clinical and functional parameters. This model was then validated in 242 consecutive patients referred between 1996 and 2001 (validation sample). In the derivation sample, sudden death was independently predicted by a model that included low-frequency power (LFP) of HRV during controlled breathing ≤13 ms 2 and left ventricular end-diastolic diameter ≥77 mm (relative risk [RR] 3.7, 95% CI 1.5 to 9.3, and RR 2.6, 95% CI 1.0 to 6.3, respectively). The derivation model was also a significant predictor in the validation sample ( P =0.04). In the validation sample, LFP ≤11 ms 2 during controlled breathing and ≥83 ventricular premature contractions per hour on Holter monitoring were both independent predictors of sudden death (RR 3.0, 95% CI 1.2 to 7.6, and RR 3.7, 95% CI 1.5 to 9.0, respectively). Conclusions— Reduced short-term LFP during controlled breathing is a powerful predictor of sudden death in patients with CHF that is independent of many other variables. These results refine the identification of patients who may benefit from prophylactic implantation of a cardiac defibrillator.

We sought to evaluate whether contrast-enhanced Doppler echocardiography can improve the noninvasive estimation of hemodynamic variables in left ventricular (LV) dysfunction. Right-heart catheterization and Doppler echocardiography were simultaneously performed in 45 patients with LV dysfunction (ejection fraction: 29 ± 7%) in sinus rhythm. Noninvasive variables were estimated as follows: cardiac output by pulsed Doppler of LV outflow tract; pulmonary capillary wedge pressure by a regression equation including mitral and pulmonary venous flow variables; pulmonary artery mean pressure from the calculated systolic and diastolic pulmonary artery pressures; and pulmonary vascular resistance from the previous measurements according to hemodynamic definition. Contrast enhancement increased the feasibility of pulmonary capillary wedge pressure estimation from 60% to 100%; of pulmonary artery mean pressure from 42% to 91%; and of pulmonary vascular resistance from 42% to 91%. Strong correlations between invasive and noninvasive hemodynamic variables were found: r = 0.90, standard error of the estimate (SEE) 0.45 L/min for cardiac output; r = 0.90, SEE 3.1 mm Hg for pulmonary capillary wedge pressure; r = 0.93, SEE 3.7 mm Hg for pulmonary artery mean pressure; and r = 0.85 SEE 1.0 Wood units for pulmonary vascular resistance. Weaker correlations for PAMP ( r = 0.82, SEE 5.6 mm Hg) and PVR ( r = 0.66, SEE 1.7 Wood units) were apparent prior to contrast enhancement. When patients were separated according to PVR threshold values, the contrast allowed the correct placement of 88% of patients, whereas only 57% were correctly assigned without it. The contrast increased accuracy and reduced interobserver variability in the evaluation of hemodynamic variables. The contrast-enhanced study is capable of increasing the value of noninvasive hemodynamic assessment in LV dysfunction. (J Am Soc Echocardiogr 2003;16:124-31.)

Background: Low flow velocity within the left atrial appendage, as assessed by transoesophageal echocardiography, is a predictor of thromboembolism and of a low success rate of cardioversion of atrial fibrillation. However, the semi-invasive nature does limit its serial application as a screening technique. Methods and Results: We investigated the value of transthoracic second harmonic echocardiography and pulsed Doppler at baseline and after intravenous contrast injection to visualize the left atrial appendage and assess blood flow velocities within its cavity. We studied 51 consecutive patients undergoing transoesophageal echocardiography. After transoesophageal echocardiography, transthoracic second harmonic imaging was performed and the left atrial appendage was visualized in 46 patients. Interpretable pulsed Doppler tracings of left atrial appendage flow were obtained at baseline in 39 patients and in 45 patients during Levovist administration. The correlations between peak emptying velocity of left atrial appendage as measured by transoesophageal echocardiography and by transthoracic standard and contrast-enhanced Doppler were 0·81 and 0·91, respectively. The agreement between transoesophageal echocardiography and transthoracic contrast-enhanced pulsed Doppler echocardiography in classifying left atrial appendage flow velocity patterns was 93%. Left atrial appendage thrombus was detected by transthoracic second harmonic imaging in only one of the eight patients shown by transoesophageal echocardiography to have a thrombus. However, all but one of the patients with left atrial appendage thrombus and/or spontaneous echocardiographic contrast at transoesophageal echocardiography had

Besides being complicated reality,in my experience, is odd . . ..Of course anyone can be simpleif he has no facts to bother aboutC. S. LewisHeart failure is haemodynamically characterized byelevated left ventricular filling pressure. Its determi-nation is important in order to optimize unloadingtherapy, interpret equivocal symptoms, predict prog-nosis and the follow-up of treatments

Background and aims: In patients with chronic congestive heart failure a high pulmonary artery wedge pressure (PAWP) is associated with poor prognosis, severe symptoms and low exercise tolerance. When atrial fibrillation is present the non-invasive prediction of PAWP by Doppler echocardiography is generally considered to be not reliable. Methods: In 51 consecutive patients with chronic heart failure, due to either ischemic and non-ischemic dilated cardiomyopathy, and atrial fibrillation simultaneous Doppler echocardiographic and hemodynamic studies were used to estimate PAWP. The power of the obtained multivariate equation was compared with that of previously developed equations and was then prospectively tested in a group of 15 patients. Results: The deceleration rate (DR) of early diastolic mitral flow, the left ventricular iso-volumic relaxation time (IVRT) and the systolic fraction of pulmonary venous flow (SF) were independent predictors of PAWP and the following multivariable equation was derived: PAWP - 24.04 + 1.23 × DR − 0.089 × IVRT − 0.175 × SF. The correlation between invasive PAWP and the PAWP non-invasively estimated by this equation in the testing group was 0.91 (standard error of estimate - 3.2 mmHg). The mean difference was 0.93 and the standard error of differences was 2.7 mmHg. Conclusion: In patients with chronic heart failure due to dilated cardiomyopathy who are in atrial fibrillation a relatively accurate estimation of PAWP can be obtained by Doppler echocardiography of mitral and pulmonary venous flow.

We compared orthotopic heart transplantation (HT) by bicaval technique with the standard technique. Between January 1995 and December 1997, 117 patients underwent 118 HTs; 71 patients (15 women and 56 men) had 72 HTs by standard technique and 46 patients (9 women, 37 men) underwent HT using bicaval procedures. Preoperative parameters were similar in both groups; 5 patients who underwent the standard technique and no patients who underwent bicaval procedures required permanent pacemakers (p = NS). Isoproterenol infusion was significantly longer in the standard technique. Major perioperative arrhythmias (ventricular tachycardia and fibrillation, asystole) appeared in 8.2% and 7.0% of standard and bicaval HTs, respectively; atrial fibrillation appeared in 13.1% and 4.6%, respectively (p = NS). At 1 month, mitral and tricuspid regurgitation rates were higher in the standard group (p = NS); at 1 year only tricuspid regurgitation was still higher (p = NS). Right atrial pressure, Wood units, cardiac output, and cardiac index were examined (p = NS). At multivariate analysis, interaction between preoperative Wood units and transplant type was elicited for Wood units at 1 month and for right atrial pressure at 1, 3, and 6 months. In the high resistance subgroup, the patients who underwent bicaval procedures had higher resistances at 1 month. In the low resistance subgroup, right atrial pressure was higher in patients who underwent standard techniques at 1, 3, and 6 months follow-up. Thus, bicaval HT was found to be safe, without surgically related complications, it provoked significantly less blood loss, and required less isoproterenol use. No significant advantages were observed in conduction disturbances and major arrhythmias or regarding the need for temporary or permanent pacemakers.

We present a new approach to constrained quadratic binary programming. Dual bounds are computed by choosing appropriate global underestimators of the objective function that are separable but not necessarily convex. Using the binary constraint on the variables, the minimization of this separable underestimator can be reduced to a linear minimization problem over the same set of feasible vectors. For most combinatorial optimization problems, the linear version is considerably easier than the quadratic version. We explain how to embed this approach into a branch-and-bound algorithm and present experimental results.

The principal idea of this paper is to exploit Semidefinite Programming (SDP) relaxation within the framework provided by Mixed Integer Nonlinear Programming (MINLP) solvers when tackling Binary Quadratic Problems. We included the SDP relaxation in a state-of-the-art MINLP solver as an additional bounding technique and demonstrated that this idea could be computationally useful. The Quadratic Stable Set Problem is adopted as the case study. The tests indicate that the Hybrid SDP Bounding Procedure allows an average 50% cut of the overall computing time and a cut of more than one order of magnitude for the branching nodes.

Transmitral flow velocity patterns evaluated by Doppler echocardiography provide important hemodynamic and prognostic information in various cardiac conditions. However, these patterns may change over time, and so far the hemodynamic and prognostic significance of these changes has not been established. Accordingly, we performed this study to determine the hemodynamic and prognostic value of changes in transmitral flow velocity patterns after 6 months of optimized medical treatment in patients with chronic heart failure due to ischemic or nonischemic dilated cardiomyopathy. Ninety-eight consecutive patients with chronic heart failure underwent a clinical examination, a cardiopulmonary exercise test, and simultaneous Doppler echocardiographic and hemodynamic studies at baseline and after 6 months of optimized medical therapy. After the examination at 6 months, patients were followed up for 12 ± 7 months. Cardiac death and heart transplantation while patients were in critical condition were considered events. A restrictive pattern was defined by an early-to-late peak diastolic velocity ratio >1 and an early diastolic deceleration time ≤ 130 msec. Patients were grouped according to their mitral flow pattern at baseline and its changes after chronic optimized therapy. No significant changes in clinical, ergometric, and hemodynamic variables were found after 6 months in the 49 patients who had a persistent restrictive transmitral flow pattern or the 24 patients who had a persistent nonrestrictive transmitral flow pattern. In the 19 patients who had a restrictive pattern at baseline that reverted into a nonrestrictive pattern, this change was accompanied by a highly significant reduction in pulmonary wedge pressure (from 25 ± 7 mm Hg to 11 ± 3 mm Hg) and by an increase in exercise capacity, whereas in the 6 patients who had a nonrestrictive pattern that became restrictive, hemodynamic features markedly deteriorated. Seventeen of the 21 events occurred in the 49 patients (event rate 35%) with a persistent restrictive pattern, whereas the event rate was much lower in the 19 patients with a reversible restrictive pattern (5%) and in the 24 patients with a persistent nonrestrictive pattern (4%). Two (33%) of the 6 patients in whom a restrictive pattern developed had events. Cox analysis revealed that a restrictive transmitral flow pattern ( p = 0.0068) and peak rate of oxygen consumption ( p = 0.0056) detected at the late examination were significantly related to cardiac events. These results show that in patients with chronic heart failure, changes in transmitral flow patterns after chronic optimized therapy are correlated with changes in pulmonary wedge pressure, are accompanied by changes in functional capacity, and provide relevant independent prognostic information.

Noninvasive cardiac output estimation by Doppler echocardiography was compared with thermodilution and Fick oxygen methods in 73 patients with advanced chronic congestive heart failure due to dilated cardiomyopathy. In these patients, Doppler echocardiographic measurements showed a closer agreement with Fick measurements than that of thermodilution.

Aims Several echo-Doppler parameters, particularly the E / e ′ ratio, have been explored in the attempt to improve prognostic stratification in chronic heart failure (CHF) patients. In most studies, however, left ventricular filling pressure was not measured and patients with severe impairment of left ventricular function were not considered. The aim of this study was to assess the prognostic value of E / e ′ when compared with both traditional echo-Doppler parameters and pulmonary wedge pressure (PWP) in patients with advanced CHF. Methods and results Right heart catheterization and a two-dimensional echo-Doppler examination were performed at baseline in 49 patients (male: 88%, age: 53 ± 9 years, New York Heart Association class: 2.7 ± 0.7, left ventricular ejection fraction: 29 ± 7%). Traditional pulsed-wave and tissue Doppler velocity parameters (DT, E , SFPVF, E ′, and E / e ′) were measured. Endpoint of survival analysis was cardiac death or urgent transplantation. During a median follow-up of 47 months (range: 1–58), 18 patients had experienced a major event (cardiac death or urgent transplantation). Both DT and E / e ′ were significantly and independently associated with the outcome (the Cox analysis), but the strength of the association was stronger for the latter ( P = 0.008 vs. P = 0.03). Moreover, DT became non-significant when adjusted for PWP, whereas E / e ′ preserved its prognostic value ( P = 0.04). The prognostic value of E ′ and PWP was borderline non-significant or clearly non-significant in both univariate and multivariable analyses. Conclusion Among the echo-Doppler parameters, E / e ′ shows the highest predictive value in patients with advanced CHF and provides prognostic information independent of PWP. These results support the use of the feasible and easy obtainable E / e ′ ratio as a prognostic indicator in these patients.

The recent technical developments in multislice computed tomography (MSCT), with ECG retro-gated image reconstruction, have elicited great interest in the possibility of accurate non-invasive imaging of the coronary arteries. The latest generation of MSCT systems with 8-16 rows of detectors permits acquisition of the whole cardiac volume during a single 15-20 s breath-hold with a submillimetric definition of the images and an outstanding signal-to-noise ratio. Thus the race which, between MSCT, electron beam computed tomography and cardiac magnetic resonance imaging, can best provide routine and reliable imaging of the coronary arteries in clinical practice has recommenced. Currently available MSCT systems offer different options for both cardiac image acquisition and reconstruction, including multiplanar and curved multiplanar reconstruction, three-dimensional volume rendering, maximum intensity projection, and virtual angioscopy. In our preliminary experience including 176 patients suffering from known or suspected coronary artery disease, MSCT was feasible in 161 (91.5%) and showed a sensitivity of 80.4% and a specificity of 80.3%, with respect to standard coronary angiography, in detecting critical stenosis in coronary arteries and artery or venous bypass grafts. These results correspond to a positive predictive value of 58.6% and a negative predictive value of 92.2%. The true role that MSCT is likely to play in the future in non-invasive coronary imaging is still to be defined. Nevertheless, the huge amount of data obtainable by MSCT along with the rapid technological advances, shorter acquisition times and reconstruction algorithm developments will make the technique stronger, and possible applications are expected not only for non-invasive coronary angiography, but also for cardiac function and myocardial perfusion evaluation, as an all-in-one examination.

A significant improvement in the noninvasive evaluation of coronary anatomy has been obtained after the introduction of the new high-speed multislice computed tomography systems. Images are reconstructed using retrospective ECG-gated protocol along with contrast analysis and three-dimensional display algorithms. The 8 detectors and the reduced tube rotation time of last-generation scanners allow the coverage of the entire heart during a single breath-hold following an intravenous bolus of 120 ml of nonionic contrast. Faster computer software offers submillimeter resolution reconstructions and increased post-processing capabilities, such as quantitative angiography, virtual angioscopy, and calcium score evaluation. At least in this phase of technical development the visualization of side branches of coronary vessels seems to advantage multislice computed tomography with respect to nuclear magnetic resonance and electron-beam computed tomography in the challenge for clinical noninvasive evaluation of coronary microcirculation.

Objective: Strenuous exercise variably modifies cardiovascular function. Only few data are available on intermediate levels of effort. We therefore planned a study in order to address the hypothesis that a half marathon distance would result in transient changes of cardiac mechanics, neural regulation and biochemical profile suggestive of a complex, integrated adaptation. Methods: We enrolled 35 amateur athletes (42 ±7 years). Supine and standing heart rate variability and a complete echocardiographic evaluation were assessed on site after the completion of a half marathon (postrace) and about 1 month after (baseline). Biochemical tests were also measured postrace. Results: Compared to baseline, the postrace left ventricular end-diastolic volume was smaller, peak velocity of E wave was lower, peak velocity of A wave higher, and accordingly the E/A ratio lower. The postrace heart and respiratory rate were higher and variance of RR interval lower, together with a clear shift towards a sympathetic predominance in supine position and a preserved response to orthostasis. At baseline, athletes were characterised by a lower, although still predominant, sympathetic drive with a preserved physiological response to standing. Conclusions: Immediately after a half marathon there are clear marks that an elevated sympathetic cardiac drive outlasts the performance, together with decreased left ventricular diastolic volumes and slight modifications of the left ventricular filling pattern without additional signs of diastolic dysfunction or indices of transient left or right ventricular systolic abnormalities. Furthermore, no biochemical indices of any permanent cardiac damage were found.

Background Mitral flow velocity patterns (MFVPs) evaluated by Doppler echocardiography are strong predictors of survival in various cardiac diseases. However, MFVPs may change over time according to loading conditions. We performed this prospective study to assess whether changes in MFVP induced by loading manipulations provided additional prognostic information in 173 patients with chronic heart failure. Methods and Results Simultaneous Doppler echocardiographic and right-sided hemodynamic recordings were obtained at baseline in all patients, during nitroprusside infusion in the 98 patients who had a baseline restrictive (early-to-late flow velocity ratio >1 and deceleration time ≤130 ms) MFVP, and during passive leg lifting in the 75 patients who had a baseline nonrestrictive MFVP. Patients were categorized, according to changes in MFVP, into four groups: 61 patients with an irreversible restrictive, 37 with a reversible restrictive, 48 patients with a stable nonrestrictive, and 27 patients with an unstable nonrestrictive MFVP. Fifty patients experienced major cardiac events. Cox analysis revealed that MFVP was a strong predictor of events and that the response to loading manipulations improved its prognostic value. Patients with an irreversible restrictive MFVP had a higher event rate (51%) than patients with a reversible restrictive MFVP (19%). Among patients with a baseline nonrestrictive MFVP, those with a stable nonrestrictive MFVP had the lowest event rate (6%), whereas the event rate was 33% in patients with an unstable nonrestrictive MFVP. Conclusions In patients with chronic heart failure, MFVPs provide independent prognostic information. Their prognostic value can be further increased by assessment of the changes induced in them by loading manipulations.

In conclusion, our findings demonstrate that right ventricular function in patients with chronic heart failure due to dilated cardiomyopathy can be reliably assessed by an echocardiographic ABD technique, which is superior to conventional manual echocardiographic methods. This technique, providing a real-time display of right ventricular function without exposure to radiation, offers important advantages when compared with radionuclide ventriculography. For these reasons, we believe that in patients with heart failure, the ABD technique will have an expanding role in noninvasively assessing right ventricular function.