Flow Mediated Dilation in Systemic Sclerosis: Association with clinical findings, capillaroscopic patterns and endothelial circulating markers.

AIM: Endothelial dysfunction represents a key feature of the pathological process underlying micro and macro-vascular damage in Systemic Sclerosis (SSc). This study aims to improve knowledge of the physiopathology of vascular damage in SSc through the assessment of the endothelial dysfunction by Flow Mediated Dilation (FMD) and serum levels of circulating endothelial dysfunction markers and the correlation of macrovascular damage with clinical findings and microvascular capillaroscopic patterns. METHODS: 57 SSc patients and 37 healthy subjects were recruited. All included subjects underwent radial artery FMD test and Nailfold Video-Capillaroscopy; serum levels of Vascular Endothelial Growth Factor (VEGF), Vascular Cell Adhesion Molecule-1 (VCAM-1) and angiopoietin-2 were evaluated. RESULTS: Compared to healthy subjects, in SSc patients lower FMD and higher time needed to obtain the maximal FMD responsewere observed, whereas serum levels of VEGF, VCAM-1, and angiopoietin-2 were significantly higher. The impairment of FMD values was associated with disease duration, pulmonary arterial hypertension, and digital ulcers and correlates with greater microvascular damage evaluated by Nailfold Video-Capillaroscopy… An inverse relationship between VEGF, angiopoietin-2, VCAM-1 levels and FMD was observed, but only VEGF and angiopoietin-2 were significantly higher in patients with digital ulcers and pulmonary arterial hypertension. CONCLUSIONS: FMD ultrasound test and circulating levels of endothelial dysfuncion markers could be useful as biomarkers of vasculopathy and could be a helpful tool in the overall assessment of vascular injury in Systemic Sclerosis patients.

Clinical course of hypertrophic cardiomyopathy patients implanted with a transvenous or subcutaneous defibrillator.

AIMS: The implantable cardioverter-defibrillator (ICD) is a life-saving therapy in patients with hypertrophic cardiomyopathy (HCM) at risk of sudden cardiac death. Implantable cardioverter-defibrillator complications are of concern. The subcutaneous ICD (S-ICD) does not use transvenous leads and is expected to reduce complications. However, it does not provide bradycardia and anti-tachycardia pacing (ATP). The aim of this study was to compare appropriate and inappropriate ICD interventions, complications, disease-related adverse events and mortality between HCM patients implanted with a S- or transvenous (TV)-ICD. METHODS AND RESULTS: Consecutive HCM patients implanted with a S- (n = 216) or TV-ICD (n = 211) were enrolled. Propensity-adjusted cumulative Kaplan-Meier curves and multivariate Cox proportional hazard ratios were used to compare 5-year event-free survival and the risk of events. The S-ICD patients had lower 5-year risk of appropriate (HR: 0.32; 95%CI: 0.15-0.65; P = 0.002) and inappropriate (HR: 0.44; 95%CI: 0.20-0.95; P = 0.038) ICD interventions, driven by a high incidence of ATP therapy in the TV-ICD group. The S- and TV-ICD patients experienced similar 5-year rate of device-related complications, albeit the risk of major lead-related complications was lower in S-ICD patients (HR: 0.17; 95%CI: 0.038-0.79; P = 0.023). The TV- and S-ICD patients displayed similar risk of disease-related complications (HR: 0.64; 95%CI: 0.27-1.52; P = 0.309) and mortality (HR: 0.74; 95%CI: 0.29-1.87; P = 0.521). CONCLUSION: Hypertrophic cardiomyopathy patients implanted with a S-ICD had lower 5-year risk of appropriate and inappropriate ICD therapies as well as of major lead-related complications as compared to those implanted with a TV-ICD. Long-term comparative follow-up studies will clarify whether the lower incidence of major lead-related complications will translate into a morbidity or survival benefit.

Incremental Value of Right Atrial Strain Analysis to Predict Atrial Fibrillation Recurrence After Electrical Cardioversion.

BACKGROUND: Although the assessment of left atrial (LA) mechanics has been reported to refine atrial fibrillation (AF) risk prediction, it doesn't completely predict AF recurrence. The potential added role of right atrial (RA) function in this setting is unknown. Accordingly, this study sought to evaluate the added value of RA longitudinal reservoir strain (RASr) for the prediction of AF recurrence after electrical cardioversion (ECV). METHODS: We retrospectively studied 132 consecutive patients with persistent AF who underwent elective ECV. Complete two-dimensional and speckle-tracking echocardiography analyses of LA and RA size and function were obtained in all patients before ECV. The end point was AF recurrence. RESULTS: During a 12-month follow-up, 63 patients (48%) showed AF recurrence. Both LASr and RASr were significantly lower in patients experiencing AF recurrence than in patients with persistent sinus rhythm (LASr, 10% ± 6% vs 13% ± 7%; RASr, 14% ± 10% vs 20% ± 9%, respectively; P < .001 for both). Right atrial longitudinal reservoir strain (area under the curve = 0.77; 95% CI, 0.69-0.84; P < .0001) was more strongly associated with the recurrence of AF after ECV than LASr (area under the curve = 0.69; 95% CI, 0.60-0.77; P < .0001). Kaplan-Meier curves showed that patients with both LASr ≤ 10% and RASr ≤ 15% had a significantly increased risk for AF recurrence (log-rank, P < .001). However, at multivariable Cox regression, RASr (hazard ratio, 3.26; 95% CI, 1.73-6.13; P < .001) was the only parameter independently associated with AF recurrence. Right atrial longitudinal reservoir strain was more strongly associated with the occurrence of AF relapse after ECV than LASr, and LA and RA volumes. CONCLUSION: Right atrial longitudinal reservoir strain was independently and more strongly associated than LASr with AF recurrence after elective ECV. This study highlights the importance of assessing the functional remodeling of both the RA and LA in patients with persistent AF.

Diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy: a multicentre network study.

AIM: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival. METHODS AND RESULTS: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival. CONCLUSIONS: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself.

Vitamin D Status and Psoriatic Arthritis: Association with the Risk for Sacroiliitis and Influence on the Retention Rate of Methotrexate Monotherapy and First Biological Drug Survival-A Retrospective Study.

A growing body of evidence on the importance of vitamin D in immune modulation has increased the interest in its possible impact on the course of rheumatological diseases. The scope of our study is to assess if the presence of different statuses of vitamin D could interfere in the clinical subsets, in methotrexate monotherapy discontinuation, and biological drug (b-DMARDs) survival in psoriatic arthritis patients (PsA). We conducted a retrospective study on PsA patients and split them into three groups based on their vitamin D status: the group with 25(OH)D ≤ 20 ng/mL, the group with levels of 25(OH)D between 20 and 30 ng/mL, and the group with serum levels of 25(OH)D ≥ 30 ng/mL. All patients were required to fulfill the CASPAR criteria for psoriatic arthritis and to have the evaluation of vitamin D serum levels at baseline visit and at clinical follow-up visits. The exclusion criteria were ages less than 18 years old, the presence of HLA B27, and satisfaction of rheumatoid arthritis classification criteria (during the study time). Statistical significance was set at p ≤ 0.05. Furthermore, 570 patients with PsA were screened and 233 were recruited. A level of 25(OH)D ≤ 20 ng/mL was present in 39% of patients; levels of 25(OH)D between 20 and 30 ng/mL presented in 25% of patients; 65% of patients with sacroiliitis presented 25 (OH)D ≤ 20 ng/mL. Methotrexate monotherapy discontinuation for failure was higher in the group with 25 (OH)D ≤ 20 ng/mL (survival time: 92 ± 10.3 weeks vs. 141.9 ± 24.1 weeks vs. 160.1 ± 23.6 weeks; p = 0.02) with higher discontinuation risk (HR = 2.168, 95% CI 1.334, 3.522; p = 0.002) than those with 25(OH)D between 20 and 30 ng/mL and those with 25(OH)D ≥ 30 ng/mL. Significantly shorter survival of first b-DMARDs was assessed in the group with 25 (OH)D ≤ 20 ng/mL versus the other groups (133.6 ± 11 weeks vs. 204.8 ± 35.8 weeks vs. 298.9 ± 35.4; p = 0.028) (discontinuation risk 2.129, 95% CI 1.186, 3.821; p = 0.011). This study highlights significant differences in clinical presentation, in particular sacroiliac involvement and on drug survival (methotrexate and b-DMARDs) in PsA patients with vitamin D deficiency. Further prospective studies, including a larger sample of patients, are needed to validate these data and to assess if the supplementation of vitamin D could improve the b-DMARDs response in PsA patients.

Bone Involvement in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide variability of clinical manifestations due to the potential involvement of several tissues and internal organs, with a relapsing and remitting course. Dysregulation of innate and adaptive immune systems, due to genetic, hormonal and environmental factors, may be responsible for a broad spectrum of clinical manifestations, affecting quality of life, morbidity and mortality. Bone involvement represents one of the most common cause of morbidity and disability in SLE. Particularly, an increased incidence of osteoporosis, avascular necrosis of bone and osteomyelitis has been observed in SLE patients compared to the general population. Moreover, due to the improvement in diagnosis and therapy, the survival of SLE patient has improved, increasing long-term morbidities, including osteoporosis and related fractures. This review aims to highlight bone manifestations in SLE patients, deepening underlying etiopathogenetic mechanisms, diagnostic tools and available treatment.

Unmasking the prevalence of amyloid cardiomyopathy in the real world: results from Phase 2 of the AC-TIVE study, an Italian nationwide survey.

AIM: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions. METHODS AND RESULTS: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%. CONCLUSION: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy.

Preliminary Data on Post Market Safety Profiles of COVID 19 Vaccines in Rheumatic Diseases: Assessments on Various Vaccines in Use, Different Rheumatic Disease Subtypes, and Immunosuppressive Therapies: A Two-Centers Study.

An increased risk of developing severe infections has been evidenced in rheumatic disease (RD) patients, and anti-COVID-19 vaccination is strictly recommended for RD patients. However, up to now, no data are available on safety, immunogenicity and efficacy of COVID-19 vaccinations in RD patients. The possible development of adverse events (AEs), including the flare-up of underlying RD, represents a matter of growing importance. The aim of our study is to assess, in RD patients, the safety profile of different types of approved vaccines and the possible influence of immunosuppressive therapies and clinical or demographic characteristics of RD patients on development of AEs. Participants (n = 185; 30.7%) received anti-COVID-19 vaccinations, 137 with autoimmune/chronic inflammatory RD (Au/cIn-RD) and 48 with nonautoimmune/chronic inflammatory RD (no-Au/cIn-RD). AEs were recorded in 42% of patients after the first dose of vaccine, and in 26% of patients after the second dose. The most common reported AEs after anti-COVID 19 vaccines were site injection pain (17%), headache (12%), fever (12%), myalgia (10%) and fatigue (10%). Relapses of the underlying Au/c-In-RD were recorded in 2.2% of patients after the first dose of vaccine. In Au/c-In-RD the risk of developing AEs after the first dose of vaccine was lower in older patients (OR = 0.95; p = 0.001), and in the group of patients with complete control of RD (OR: 0.2; p = 0.010). A lower percentage of AEs was observed in patients with complete control of their Au/cIn-RD (29%) compared to those with low (57%) or moderate-high disease activity (63%) (p = 0.002 and p = 0.006 respectively). In this study all types of COVID-19 vaccines in use in Italy seemed safe in RD patients. The results of this study might provide reassuring information for Au/cIn RD patients and clinicians and could strengthen the data on vaccine safety to guide the use of COVID-19 vaccines in Au/cIn-RD on immunosuppressive agents.

Sudden Cardiac Death in Children Affected by Cardiomyopathies: An Update on Risk Factors and Indications at Transvenous or Subcutaneous Implantable Defibrillators.

In the present paper, we will discuss the main cardiomyopathies affecting children with a specific focus on risk stratification and prevention of sudden cardiac death (SCD). We will discuss the main clinical features of hypertrophic cardiomyopathy (HCM), dilated and restrictive cardiomyopathies, left ventricular non-compaction (LVNC) and arrhythmogenic cardiomyopathy (AC), always highlighting their peculiarities in the pediatric age. Since sudden cardiac death may be the first manifestation of the disease, even in children, the identification of the specific underlying condition and of risk factors are pivotal to carry out the appropriate preventing strategies. ICD recommendations in children are similar to adults, but supporting evidences are not so solid, being based on registries or single center studies. Furthermore, children and young patients are most likely to manifest long term complications related to an implanted ICD, and this should be taken into account when evaluating the risk benefit ratio. In this perspective, subcutaneous ICDs (S-ICDs) could carry an advantage; however, they cannot be considered in small children for technical reasons. Data on effectiveness and safety of S-ICDs in a pediatric population is still lacking, although some limited experiences are reported and will be discussed in the current review.

Partial Pericardial Agenesis Mimicking Arrhythmogenic Right Ventricular Cardiomyopathy.

Absence of the pericardium is a rare congenital disease in which the fibroserum membrane covering the heart is partially or totally absent. It is characterized by few echocardiography (ECG) and imaging features that can mislead the diagnosis to an inherited cardiac disease, such as arrhythmogenic right ventricular cardiomyopathy. Although it has often a benign course, this congenital defect should be identified as in some cases herniation and strangulation can be life-threatening and cause sudden cardiac death. Red flags on ECG (sinus bradycardia, variable T-wave inversion), chest x-ray (Snoopy sign, absence of tracheal deviation, and esophagus impression), and transthoracic echocardiogram (unusual windows, teardrop left ventricle, and elongated atria) should rise the suspicion of pericardium absence. The correct diagnosis, confirmed by cardiac magnetic resonance, is mandatory as the consequences on the sport activity certification, the management, and the treatment are extremely different.

Prevalence of cardiac amyloidosis among adult patients referred to tertiary centres with an initial diagnosis of hypertrophic cardiomyopathy.

BACKGROUND: Differential diagnosis of genetic causes of left ventricular hypertrophy (LVH) is crucial for disease-specific therapy. We aim to describe the prevalence of Cardiac Amyloidosis (CA) among patients ≥40 years with an initial diagnosis of HCM referred for second opinion to national cardiomyopathy centres. METHODS: Consecutive patients aged ≥40 years referred with a tentative HCM diagnosis in the period 2014-2017 underwent clinical evaluation and genetic testing for HCM (including trans-thyretin-TTR). Patients with at least one red flag for CA underwent blood/urine tests, abdominal fat biopsy and/or bone-scintigraphy tracing and eventually ApoAI sequencing. RESULTS: Out of 343 patients (age 60 ±â€¯13 years), 251 (73%) carried a likely/pathogenic gene variant, including 12 (3.5%) in the CA-associated genes TTR (n = 11) and ApoAI (n = 1). Furthermore, 6 (2%) patients had a mutation in GLA. Among the remaining, mutation-negative patients, 26 with ≥1 CA red-flag were investigated further: 3 AL-CA and 17 wild-type-TTR-CA were identified. Ultimately, 32(9%) patients were diagnosed with CA. Prevalence of CA increased with age: 1/75 (1%) at age 40-49, 2/86 (2%) at age 50-59, 8/84 (9%) at age 60-69, 13/61 (21%) at age 70-79, 8/31 (26%) at age ≥80 (p for trend <0.01). CONCLUSIONS: Among patients referred with and initial diagnosis of HCM, CA was the most common unrecognized mimic (9% prevalence) and increased with age (from 1% at ages 40-49 years to 26% >80 years). Age at diagnosis should be considered one of the most relevant red flags for CA in patients with HCM phenotypes; however, there is no clear age cut-off mandating scintigraphy and other second level investigations in the absence of other features suggestive of CA.

Correlation between pulmonary artery pressure and thoracic impedance: Insights from daily monitoring through an implanted device in chronic heart failure.

BACKGROUND: Thoracic impedance (TI) decrease and pulmonary artery pressure (PAP) elevation precede acute decompensation in congestive heart failure (HF). However, the relationship between TI and PAP has been studied only in the context of acute decompensation. METHODS: This prospective, observational study enrolled subjects with reduced ejection fraction HF, previously implanted with an ICD capable of measuring TI. Patients underwent implantation of a sensor for direct measurement of PAP (CardioMEMs™). Both TI and PAP were remotely monitored daily during follow up. Investigators were blinded to PAP values during the first three months, then PAP was used as a guide to therapy. RESULTS: Ten patients were followed up for 405±141days (3720 patient-days). During hemodynamic guided therapy, diastolic PAP (dPAP) decreased from 27.8±10.2mmHg to 24.0±8.0mmHg (p<0.001); non-significant variations of TI were observed. A significant negative correlation was found between the variations of TI and PAP vs. baseline (p<0.001). Episodes of sustained increase of PAP preceded subsequent periods of TI decrease by 5.6±3.9days, but the former were poor predictors of the latter (sensitivity 0.37). CONCLUSIONS: Our study confirms the strict correlation that exists between left ventricular filling pressures and lung water content, estimated by dPAP and TI, respectively. However, dPAP acute variation analysis showed a limited value in predicting subsequent episodes of TI decrease.

Retrospective application of Program to Access and Review Trending iNformation and Evaluate coRrelation to Symptoms in patients with Heart Failure criteria for the remote management of patients with cardiac resynchronisation therapy.

Aim The Program to Access and Review Trending iNformation and Evaluate coRrelation to Symptoms in patients with Heart Failure (PARTNERS HF) trial elaborated a multiparametric model for prediction of acute decompensation in advanced heart failure patients, based on periodical in office data download from cardiac resynchronisation devices. In this study, we evaluated the ability of the PARTNERS HF criteria to detect initial decompensation in a population of moderate heart failure patients under remote monitoring. Methods We retrospectively applied the PARTNERS HF criteria to 1860 transmissions from 104 patients (median follow up 21 months; range 1-67 months), who were enrolled in our programme of telemedicine after cardiac resynchronisation therapy. We tested the ability of a score based on these criteria to predict any acute clinical decompensation occurring in the 15 days following a transmission. Results In 441 cases, acute heart failure was diagnosed after the index transmission. The area under the curve (AUC) of the score for the diagnosis of acute decompensation was 0.752 (confidence interval (CI) 95% 0.728-0.777). The best score cut-off was consistent with the results of PARTNERS HF: with a score ≥2, sensitivity was 75% and specificity 68%. The odds ratio for events was 6.24 (CI 95% 4.90-7.95; p < 0.001). Conclusions When retrospectively applied to remote monitoring transmissions and arranged in a score, PARTNERS HF criteria could identify HF patients who subsequently developed acute decompensation. These results warrant prospective studies applying PARTNERS HF criteria to remote monitoring.

Correlation between trans and intra-thoracic impedance and conductance in patients with chronic heart failure.

AIMS: In chronic heart failure, changes of intra-thoracic impedance (Z0IT) may suggest impending pulmonary congestion; a similar result has been found by measuring trans-thoracic conductance (TFCTT = 1/Z0 = 1/kΩ). We assumed that a relationship could exist between Z0IT and TFCTT. METHODS: We collected 140 measurements from 70 patients carrying an implantable cardioverter-defibrillator/cardiac resynchronization device with the CareLink function (71 ± 9 years, New York Heart Association (NYHA) 2.4 ± 0.9, ejection fraction 31 ± 8%, optimal treatment); they were studied during system alarms and after appropriate treatment (diuretics and/or vasodilators, n = 42) or during clinical stability and at the time of a system alarm (n = 28); correspondent BNP values were obtained. We related Z0IT obtained by the device, with TFCTT obtained with a commercial system. RESULTS: A strong relationship was found between Z0IT and TFCTT. Changes in the variables after treatment or during worsening conditions were of the same direction and order of magnitude, and were related to BNP levels obtained simultaneously. CONCLUSIONS: Trans-thoracic conductance, similarly to intra-thoracic impedance, may noninvasively point to pulmonary congestion and be useful in patients not carrying an implanted device. The possibility of remotely obtaining this variable should be evaluated for the telemonitoring of heart failure patients.

Prognostic value of noninvasive hemodynamic evaluation of the acute effect of levosimendan in advanced heart failure.

AIMS: Optimization of inotropic treatment in worsening heart failure sometimes requires invasive hemodynamic assessment in selected patients. Impedance cardiography (ICG) may be useful for a noninvasive hemodynamic evaluation. METHODS: ICG was performed in 40 patients (69 ± 8 years; left ventricular ejection fraction 27.5 ± 5.6%; New York Heart Association 3.18 ± 0.34; Interagency Registry for Mechanically Assisted Circulatory Support 5.48 ± 0.96, before and after infusion of Levosimendan (0.1­0.2 µg/kg per min for up to 24 h). Echocardiogram, ICG [measuring cardiac index (CI), total peripheral resistances (TPRs) and thoracic fluid content (TFC)] and plasma levels of brain natriuretic peptide (BNP) were obtained; in nine patients, right heart catheterization was also carried out. RESULTS: When right catheterization and ICG were performed simultaneously, a significant relationship was observed between values of CI and TPR, and between TFC and pulmonary wedge pressure. ICG detected the Levosimendan-induced recovery of the hemodynamic status, associated with improved systolic and diastolic function and reduction in BNP levels. One-year mortality was 4.4%. At multivariate analysis, independent predictors of mortality were: no improvement in the severity of mitral regurgitation, a persistent restrictive filling pattern (E/E' > 15), a reduction of BNP levels below 30% and a change below 10% in CI, TPR and TFC. When combined, absence of hemodynamic improvement at ICG could predict 1-year mortality with better sensitivity (86%) and specificity (85%) than the combination of echocardiographic and BNP criteria only (sensitivity 80% and specificity 36%). CONCLUSION: Noninvasive hemodynamic evaluation of heart failure patients during infusion of inodilator drugs is reliable and may help in their prognostic stratification.

Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance, and one-year survival.

The role of repeated infusions of Levosimendan (LEVO) in patients with chronic advanced heart failure is still unclear. Thirty-three patients with chronic heart failure presenting clinical deterioration were randomized 2:1 to receive monthly infusions of LEVO (n = 22) or Furosemide (Controls, n = 11). At the first drug's administration, noninvasive hemodynamic evaluation was performed; before and after each infusion, we assessed NYHA class, systolic and diastolic function, functional mitral regurgitation, and brain natriuretic peptide (BNP) levels. Noninvasive hemodynamic in the LEVO group showed vasodilation and decrease in thoracic conductance (index of pulmonary congestion), whereas in Controls, only a reduced thoracic conductance was observed. In the LEVO group, systolic and diastolic function, ventricular volumes, severity of mitral regurgitation, and BNP levels improved over time from baseline and persisted 4 weeks after the last infusion (P < 0.01). In Controls, no change developed over time in cardiac function and BNP levels. In LEVO-treated patients, 1-year mortality tended to be lower than in those treated with Furosemide. In conclusion, serial LEVO infusions in advanced heart failure improved ventricular performance and favorably modulated neurohormonal activation. Multicenter randomized studies are warranted to test the effect of LEVO on long-term outcome.