Pulmonary arterial hypertension: Navigating the pathways of progress in diagnosis, treatment, and patient care.

Pulmonary arterial hypertension (PAH) is a form of precapillary pulmonary hypertension caused by a complex process of endothelial dysfunction and vascular remodeling. If left untreated, this progressive disease presents with symptoms of incapacitating fatigue causing marked loss of quality of life, eventually culminating in right ventricular failure and death. Patient management is complex and based on accurate diagnosis, risk stratification, and treatment initiation, with close monitoring of response and disease progression. Understanding the underlying pathophysiology has enabled the development of multiple drugs directed at different targets in the pathological chain. Vasodilator therapy has been the mainstay approach for the last few years, significantly improving quality of life, functional status, and survival. Recent advances in therapies targeting dysfunctional pathways beyond endothelial dysfunction may address the fundamental processes underlying the disease, raising the prospect of increasingly effective options for this high-risk group of patients with a historically poor prognosis.

Chronic thromboembolic pulmonary hypertension: A comprehensive review of pathogenesis, diagnosis, and treatment strategies.

Chronic thromboembolic pulmonary hypertension (CTEPH) is part of group 4 of the pulmonary hypertension (PH) classification and generally affects more than a third of patients referred to PH centers. It is a three-compartment disease involving proximal (lobar-to-segmental) and distal (subsegmental) pulmonary arteries that are obstructed by persistent fibrothrombotic material, and precapillary pulmonary arteries that can be affected as in pulmonary arterial hypertension. It is a rare complication of pulmonary embolism (PE), with an incidence of around 3% in PE survivors. The observed incidence of CTEPH in the general population is around six cases per million but could be three times higher than this, as estimated from PE incidence. However, a previous venous thromboembolic episode is not always documented. With advances in multimodality imaging and therapeutic management, survival for CTEPH has improved for both operable and inoperable patients. Advanced imaging with pulmonary angiography helps distinguish proximal from distal obstructive disease. However, right heart catheterization is of utmost importance to establish the diagnosis and hemodynamic severity of PH. The therapeutic strategy relies on a stepwise approach, starting with an operability assessment. Pulmonary endarterectomy (PEA), also known as pulmonary thromboendarterectomy, is the first-line treatment for operable patients. Growing experience and advances in surgical technique have enabled expansion of the distal limits of PEA and significant improvements in perioperative and mid- to long-term mortality. In patients who are inoperable or who have persistent/recurrent PH after PEA, medical therapy and/or balloon pulmonary angioplasty (BPA) are effective treatment options with favorable outcomes that are increasingly used. All treatment decisions should be made with a multidisciplinary team that includes a PEA surgeon, a BPA expert, and a chest radiologist.

Chronic thromboembolic pulmonary hypertension: Initial experience of patients undergoing pulmonary thromboendarterectomy.

INTRODUCTION AND OBJECTIVES: Pulmonary endarterectomy (PEA) is a potentially curative procedure in patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study reports the initial experience of a Portuguese PH center with patients undergoing PEA at an international surgical reference center. METHODS: Prospective observational study of consecutive CTEPH patients followed at a national PH center, who underwent PEA at an international surgical reference center between October 2015 and March 2019. Clinical, functional, laboratory, imaging and hemodynamic parameters were obtained in the 12 months preceding the surgery and repeated between four and six months after PEA. RESULTS: 27 consecutive patients (59% female) with a median age of 60 (49-71) years underwent PEA. During a median follow-up of 34 (21-48) months, there was an improvement in functional class in all patients, with only one cardiac death. From a hemodynamic perspective, there was a reduction in mean pulmonary artery pressure from 48 (42-59) mmHg to 26 (22-38) mmHg, an increase in cardiac output from 3.3 (2.9-4.0) L/min to 4.9 (4.2-5.5) L/min and a reduction in pulmonary vascular resistance from 12.1 (7.2-15.5) uW to 3.5 (2.6-5,2) uW. During the follow-up, 44% (n=12) of patients had no PH criteria, 44% (n=12) had residual PH and 11% (n=3) had PH recurrence. There was a reduction of N-terminal pro-B-type natriureticpeptide from 868 (212-1730) pg/mL to 171 (98-382) pg/mL. Rright ventricular systolic function parameters revealed an improvement in longitudinal systolic excursion and peak velocity of the plane of the tricuspid ring from 14 (13-14) mm and 9 (8-10) cm/s to 17 (16-18) mm and 13 (11-15) cm/s, respectively. Of the 26 patients with preoperative right ventricular dysfunction, 85% (n=22) recovered. The proportion of patients on specific vasodilator therapy decreased from 93% to 44% (p<0.001) and the proportion of those requiring oxygen therapy decreased from 52% to 26% (p=0.003). The six-minute walk test distance increased by about 25% compared to the baseline and only eight patients had significant desaturation during the test. CONCLUSION: Pulmonary endarterectomy performed at an experienced high-volume center is a safe procedure with a very favorable medium-term impact on functional, hemodynamic and right ventricular function parameters in CTEPH patients with operable disease. It is possible for PH centers without PEA differentiation to refer patients safely and effectively to an international surgical center in which air transport is necessary.

Chronic thromboembolic pulmonary hypertension: initial experience of patients undergoing pulmonary thromboendarterectomy. / Hipertensão pulmonar tromboembólica crónica: experiência inicial de doentes submetidos a tromboendarterectomia pulmonar.

INTRODUCTION AND OBJECTIVES: Pulmonary endarterectomy (PEA) is a potentially curative procedure in patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study reports the initial experience of a Portuguese PH center with patients undergoing PEA at an international surgical reference center. METHODS: Prospective observational study of consecutive CTEPH patients followed at a national PH center, who underwent PEA at an international surgical reference center between October 2015 and March 2019. Clinical, functional, laboratory, imaging and hemodynamic parameters were obtained in the 12 months preceding the surgery and repeated between four and six months after PEA. RESULTS: 27 consecutive patients (59% female) with a median age of 60 (49-71) years underwent PEA. During a median follow-up of 34 (21-48) months, there was an improvement in functional class in all patients, with only one cardiac death. From a hemodynamic perspective, there was a reduction in mean pulmonary artery pressure from 48 (42-59) mmHg to 26 (22-38) mmHg, an increase in cardiac output from 3.3 (2.9-4.0) L/min to 4.9 (4.2-5.5) L/min and a reduction in pulmonary vascular resistance from 12.1 (7.2-15.5) uW to 3.5 (2.6-5, 2) uW. During the follow-up, 44% (n=12) of patients had no PH criteria, 44% (n=12) had residual PH and 11% (n = 3) had PH recurrence. There was a reduction of N-terminal pro-B-type natriureticpeptide from 868 (212-1730) pg/mL to 171 (98-382) pg/mL. Rright ventricular systolic function parameters revealed an improvement in longitudinal systolic excursion and peak velocity of the plane of the tricuspid ring from 14 (13-14) mm and 9 (8-10) cm/s to 17 (16-18) mm and 13 (11-15) cm/s, respectively. Of the 26 patients with preoperative right ventricular dysfunction, 85% (n=22) recovered. The proportion of patients on specific vasodilator therapy decreased from 93% to 44% (p<0.001) and the proportion of those requiring oxygen therapy decreased from 52% to 26% (p=0.003). The six-minute walk test distance increased by about 25% compared to the baseline and only eight patients had significant desaturation during the test. CONCLUSION: Pulmonary endarterectomy performed at an experienced high-volume center is a safe procedure with a very favorable medium-term impact on functional, hemodynamic and right ventricular function parameters in CTEPH patients with operable disease. It is possible for PH centers without PEA differentiation to refer patients safely and effectively to an international surgical center in which air transport is necessary.

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure.

BACKGROUND: Furosemide is associated with poor prognosis in patients with heart failure and reduced ejection fraction (HFrEF). AIM: To evaluate the association between daily furosemide dose prescribed during the dry state and long-term survival in stable, optimally medicated outpatients with HFrEF. POPULATION AND METHODS: Two hundred sixty-six consecutive outpatients with left ventricular ejection fraction <40%, clinically stable in the dry state and on optimal heart failure therapy, were followed up for 3 years in a heart failure unit. The end point was all-cause death. There were no changes in New York Heart Association class and therapeutics, including diuretics, and no decompensation or hospitalization during 6 months. Furosemide doses were categorized as low or none (0-40 mg/d), intermediate (41-80 mg/d), and high (>80 mg). Cox regression was adjusted for significant confounders. RESULTS: The 3-year mortality rate was 33.8%. Mean dose of furosemide was 57.3 ± 21.4 mg/d. A total of 47.6% of patients received the low dose, 42.1% the intermediate dose, and 2.3% the high dose. Receiver operating characteristics for death associated with furosemide dose showed an area under the curve of 0.74 (95% confidence interval [CI]: 0.68-0.79; P < .001), and the best cutoff was >40 mg/d. An increasing daily dose of furosemide was associated with worse prognosis. Those receiving the intermediate dose (hazard ratio [HR] = 4.1; 95% CI: 2.57-6.64; P < .001) or high dose (HR = 19.8; 95% CI: 7.9-49.6; P < .001) had a higher risk of mortality compared to those receiving a low dose. Patients receiving >40 mg/d, in a propensity score-matched cohort, had a greater risk of mortality than those receiving a low dose (HR = 4.02; 95% CI: 1.8-8.8; P = .001) and those not receiving furosemide (HR = 3.9; 95% CI: 0.07-14.2; P = .039). CONCLUSION: Furosemide administration during the dry state in stable, optimally medicated outpatients with HFrEF is unfavorably associated with long-term survival. The threshold dose was 40 mg/d.

Red blood cell distribution width is a survival predictor beyond anemia and Nt-ProBNP in stable optimally medicated heart failure with reduced ejection fraction outpatients.

BACKGROUND: RDW is an automatic value obtained with the blood count, and represents the erythrocytes dimension variation. OBJECTIVE: To evaluate in optimally medicated outpatients with heart failure with reduced ejection fraction (HFrEF) the RDW prognostic value regarding survival in a multivariable model including anemia and Nt-ProBNP. METHODS: 233 consecutive outpatients, LVEF <40%, clinically stable were followed-up for 3-years in an HF Unit. End-point was all-cause death. The RDW categorized according to the tertiles (T1 = <13.9; T2 14-15.2; T3> = 15.3). Anemia classified according to the WHO criteria. Cox survival model adjusted for clinical profile, optimal therapeutic, renal function, Nt-ProBNP, etiology, atrial fibrillation, and anemia. RESULTS: (1) The 3-years death rate was 33.5%, and increased with the RDW tertiles (17.3%; 25%; 61.1%; p < 0.001). (2) The ROC curve for death associated with RDW (AUC 0.73; p < 0.001); (3) The adjusted death risk increased with the tertiles (Hazard-ratio '[HR] = 1.61; IC 95% 1.09-2.39; p = 0.017). RDW> = 15.3 had greater adjusted death risk than T1 (HR = 2.18; 95% CI 0.99-4.8; p = 0.05) and T1+T2 (HR = 1.54; 95% CI 1.13-2.09; p = 0.006). CONCLUSION: RDW determined in optimally medicated outpatients with HFrEF, during dry-state, is a strong, cheap, and independent predictor of long-term survival.

Left atrial function index predicts long-term survival in stable outpatients with systolic heart failure.

AIMS: Left atrial (LA) function index (LAFI) is a rhythm-independent index that combines LA emptying fraction (LAEF), adjusted LA volume (LAVi), and stroke volume. We evaluated LAFI as a predictor of long-term survival in outpatients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: For 3 years, we followed up 203 outpatients with a left ventricular ejection fraction <40%, who were clinically stable and on optimal therapy. The endpoint was all-cause death. LAFI was calculated as LAFI = ([LAEF × left ventricular outflow tract-velocity time integral]/[LAVi]), and was categorized into quartiles (9.26/16.56/31.92) and median (16.57). Incremental Cox regression models adjusted for significant confounders were used for survival analyses. The 3-year death rate was 30%. Higher quartiles had lower death rates (43.1%/45.1%/25.5%/6%, P < 0.001). The receiver operating characteristic curve for death was associated with LAFI (area under curve = 0.695, 95% CI 0.62-0.77, P < 0.001). In the direct comparison with LAVi and LAEF, LAFI (HRcox 0.93, 95% CI 0.89-0.97, P < 0.001) was the only predictor of survival. LAFI (HRcox 0.95, 95% CI 0.88-1.01, P = 0.099), LAFI quartiles (HR 0.29, 95% CI 0.125-0.672, P=0.004), and LAFI ≥16.57 (HRcox 0.62, 95% CI 0.38-1.02, P=0.058) were adjusted predictors of survival. Subgroup analysis by heart rhythm (sinus vs. atrial fibrillation) showed that LAFI per unit increase and LAFI quartiles were independent predictors of death in both subgroups. CONCLUSION: LAFI determination in HFrEF stable outpatients is a predictor of long-term survival and provides increased prognostic value over a wide range of confounder risk factors.

Treatment with Optimal Dose Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Has a Positive Effect on Long-Term Survival in Older Individuals (Aged >70 Years) and Octogenarians with Systolic Heart Failure.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is a disease of older people, but the target doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are unknown. OBJECTIVE: To evaluate the association of ACEI/ARB dose level with long-term survival in stable older patients (aged >70 years) and octogenarian outpatients with HFrEF. POPULATION AND METHODS: A total of 138 outpatients aged >70 years (35.5 % > 80 years), with an LVEF <40 % and who were clinically stable on optimal therapy were followed up for 3 years. The ACEI/ARB doses were categorized as: none (0), low (1-50 % target dose), and high (50-100 % target dose). The Cox regression survival model was adjusted for age, ischemic etiology, and renal function. RESULTS: ACEIs/ARBs were prescribed to 91.3 % of patients, and 52.9 % received the high dose. Survival improved with increasing ACEI/ARB dose level in the total population (Hazard Ratio [HR] = 0.67; 95 % confidence interval [CI] 0.55-0.82; p < 0.001), older patients aged >70 years (HR = 0.65; 95 % CI 0.51-0.83; p < 0.001), and octogenarians (HR = 0.71; 95 % CI 0.51-0.99; p = 0.045). The low (HR = 0.35; 95 % CI 0.16-0.76; p = 0.008) and high doses (HR = 0.13; 95 % CI 0.06-0.32; p < 0.001) improved survival compared with not receiving ACEIs/ARBs. The high dose was associated with a better survival than the low dose in the total population (HR = 0.35; 95 % CI 0.19-0.67; p = 0.001) and in a propensity score-matched cohort (HR = 0.41; 95 % CI 0.16-1.02; p = 0.056). In octogenarians, all dose levels were associated with improved survival compared with not receiving ACEIs/ARBs, but there was no difference between ACEI/ARB doses. CONCLUSION: The achieved optimal dose of ACEIs/ARBs in ambulatory older people with HFrEF is associated with long-term survival.

Atomic force microscopy as a tool to evaluate the risk of cardiovascular diseases in patients.

The availability of biomarkers to evaluate the risk of cardiovascular diseases is limited. High fibrinogen levels have been identified as a relevant cardiovascular risk factor, but the biological mechanisms remain unclear. Increased aggregation of erythrocytes (red blood cells) has been linked to high plasma fibrinogen concentration. Here, we show, using atomic force microscopy, that the interaction between fibrinogen and erythrocytes is modified in chronic heart failure patients. Ischaemic patients showed increased fibrinogen-erythrocyte binding forces compared with non-ischaemic patients. Cell stiffness in both patient groups was also altered. A 12-month follow-up shows that patients with higher fibrinogen-erythrocyte binding forces initially were subsequently hospitalized more frequently. Our results show that atomic force microscopy can be a promising tool to identify patients with increased risk for cardiovascular diseases.

Serial measurements of the Nt-ProBNP during the dry state in patients with systolic heart failure are predictors of the long-term prognosis.

OBJECTIVE: To evaluate the long-term predictive value of serial Nt-ProBNP during dry-state in patients with systolic heart failure (SHF). METHODS: Nt-ProBNP was measured quarterly during a 6-month dry-state period in 40 SHF outpatients. EVENTS: all-cause mortality or hospitalization. FOLLOW-UP: 5 years. RESULTS: The Nt-ProBNP >1000 pg/ml (baseline and 6 months) and the variation rate (VR) >30% were independently associated with the survival and composite endpoint curve. VR >30% added significant prognostic information to the single Nt-ProBNP 1000 pg/ml cut-off. Patients with at least one Nt-ProBNP determination >1000 pg/ml were at greater risk of death. CONCLUSION: Serial Nt-ProBNP measurements in patients with SHF during the dry-state are strong predictors of the long-term prognosis.

The importance of assessing nutritional status in elderly patients with heart failure.

Heart failure (HF) is a syndrome characterized by high morbidity and mortality, despite advances in medical and device therapy that have significantly improved survival. The outcome of HF in elderly patients results from a combination of biological, functional, psychological, and environmental factors, one of which is nutritional status. Malnutrition, as well as HF, is frequently present with aging. Early detection might lead to earlier intervention. It is our goal to review the importance of nutritional status in elderly patients with HF, as well as tools for assessing it. We also propose a simple decision algorithm for the nutritional assessment of elderly patients with HF.

Heart rate reduction with ivabradine in patients with acute decompensated systolic heart failure.

INTRODUCTION: In patients with acute decompensated systolic heart failure (ADSHF) high resting heart rate (HR) could be either a compensatory mechanism or contribute to worsening heart failure. The aim of this study was to evaluate, in patients with ADSHF and resting HR >70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction. METHODS: Ten consecutive patients with ADSHF, left ventricular ejection fraction <40 % and HR >70 bpm, without other acute conditions or inotropic therapy, began open-label treatment with oral ivabradine according to a pre-established Heart Failure Unit protocol. We obtained clinical and laboratory data at four periods: admission (T0), immediately before initiation of ivabradine (T2), 24 h after initiation of ivabradine (T3), and at discharge (T4). RESULTS: Ivabradine was administered in 60 % of the patients before the second day. HR decreased 10.7 ± 7.2 bpm at T3 (p < 0.001) and 16.3 ± 8.2 bpm at T4 (p = 0.002). The systolic blood pressure decreased at T3 (p = 0.012), returning to baseline values at T4. There was no change in diastolic and mean blood pressure. New York Heart Association (NYHA) class improvement by two levels was associated with lower HR at T4 (p = 0.033). HR and N-terminal pro-brain natriuretic peptide (Nt-ProBNP) at baseline correlated significantly [Spearman correlation coefficient (rs) = 0.789, p = 0.013]. Total Nt-ProBNP reduction correlated with the HR before (r = 0.762, p = 0.028) and after (T3: r = 0.647, p = 0.083; T4: r = 0.738, p = 0.037) ivabradine addition. CONCLUSION: In the present cohort of patients with ADSHF and HR >70 bpm, the selective reduction of HR with oral ivabradine was safe and efficient.

Early NT-proBNP decrease with ivabradine in ambulatory patients with systolic heart failure.

BACKGROUND: Heart rate (HR) reduction in patients with systolic heart failure (HF) is a cornerstone of current therapy. The aim of this study was to evaluate the short-term effect of the HR reduction with ivabradine on N-terminal pro-brain natriuretic peptide (NT-proBNP) in outpatients with systolic HF. HYPOTHESIS: Ivabradine improves survival and promotes left ventricle remodelling by reducing resting heart rate. Nt-ProBNP absolute and trends predict prognosis. We hypothesized a possible association between heart rate decrease and Nt-ProBNP values. METHODS: We included 25 outpatients with systolic HF on optimized medical therapy (80% on angiotensin-converting enzyme inhibitors, 56% on spironolactone, and 88% on ß-blocker therapy), left ventricle ejection fraction <40%, and sinus rhythm and HR >70/bpm. After a 1 month running-out period, to establish the clinical and NT-proBNP stability, patients were started on ivabradine for 3 months. RESULTS: Ivabradine decreased NT-proBNP (P = 0.002) from a median of 2850 pg/mL to 1802 pg/mL, corresponding to a median absolute and percent decrease of 964 pg/mL and 44.5%, respectively. The baseline HR correlated significantly with the baseline NT-proBNP (rs = 0.411, P = 0.041). The absolute and percent HR decrease correlated with the absolute NT-proBNP decrease (rs = 0.442, P = 0.027; rs = 0.395, P = 0.05). The greater the NT-proBNP absolute decrease tertile, the greater the baseline HR (P = 0.023) and the absolute (P = 0.028) and percent (P = 0.064) HR variation. CONCLUSIONS: In outpatients with systolic HF, the NT-proBNP reduction obtained by short-term ivabradine treatment correlates closely with the degree of HR reduction.

Effectiveness and safety of levosimendan in clinical practice.

BACKGROUND: In previous randomized studies levosimendan improved hemodynamics and clinical course, with a still unclear effect on prognosis. There are, however, few data regarding its effects when used in daily practice. AIMS: We evaluated the clinical effectiveness and safety of levosimendan in the treatment of acute systolic heart failure (SHF) in daily practice conditions. METHODS: In this prospective, multicenter, nonrandomized trial, a continuous infusion of levosimendan (0.05 microg/kg/min-0.2 microg/kg/min) was administered for 24 hours. An optional loading dose of 12 microg/kg over 10 minutes was used. The primary combined endpoint of clinical effectiveness (as defined by a eight-variable clinical score) and safety (defined by the absence of serious adverse events) was assessed at 24 hours after the beginning of treatment; a second similar primary combined endpoint was assessed at 5 days. RESULTS: One hundred and twenty-nine consecutive patients requiring inotropes despite optimal oral background heart failure therapy were recruited. The primary endpoint was reached in 80.6% at 24 hours and in 79.7% at 5 days. During the six months before levosimendan the number of patient days of hospitalization for heart failure was 14.9 +/- 14.6 versus 3.1 +/- 7.6 during the six months following levosimendan (p < 0.001). CONCLUSIONS: In daily practice, levosimendan was clinically effective and safe in 80.6% and 79.7% of patients with acute SHF at 24 hours and 5 days respectively after the beginning of treatment. A marked reduction in the number of days of hospitalization for heart failure was also seen during the subsequent six months.

Anomalous origin of the circumflex coronary artery--two case reports.

As shown in many series, congenital coronary artery anomalies are found in 0.6 to 1.5% of patients undergoing coronary angiography. Various types of coronary anomalies have been described, many involving the circumflex artery. The second most common anomaly is of the circumflex arising from the right sinus of Valsalva, while origin in the right coronary artery is also frequent. The most common anomaly is absence of the left main coronary artery, the anterior descending and circumflex arteries originating separately in the left coronary sinus. Such anomalies are usually benign, although earlier and more aggressive atherosclerosis is more likely than in normal coronaries and myocardial ischemia can result. Although rare, this can manifest as sudden death. Conventional coronary angiography may be unable to determine the three-dimensional course of the anomalous vessel. The development of multislice computed tomography and its application to cardiac imaging mean that it is now possible to visualize the coronary arteries non-invasively and to obtain more accurate information on their proximal course. We present two cases of congenital anomaly of the circumflex coronary artery diagnosed with the aid of multislice computed tomography.

Levosimendan in daily intensive care practice--the experience of 15 centers. Background, methods and organization of the PORTLAND study.

INTRODUCTION: The LIDO and RUSSLAN trials showed that levosimendan was well tolerated and had a stronger hemodynamic effect than dobutamine and a positive impact on prognosis. There are, however, few data regarding its effectiveness and safety when used in an everyday clinical setting. OBJECTIVE: To test the hypothesis that in day-to-day practice conditions levosimendan is both effective and safe for the treatment of decompensated heart failure (HF). This primary combined endpoint of effectiveness and safety was evaluated at 24 hours and 5 days after the beginning of the treatment. DESIGN: Prospective, multicenter, nonrandomized clinical trial with evaluations at baseline, 24 hours, 5 days, and 3 and 6 months. Follow-up for 6 months. SETTING: The intensive care units of 15 cardiology or internal medicine departments. PATIENTS: 129 consecutive patients requiring inotropes due to decompensated systolic HF despite maximally tolerated oral therapy. INTERVENTION: 24-hour infusion of levosimendan via a central or peripheral vein. MEASUREMENTS AND EVALUATION OF RESULTS: 1. Monitoring: Continuous ECG monitoring, non-invasive blood pressure, urinary output, oximetry. Invasive monitoring was not required. 2. Follow-up. Baseline evaluation: history, physical examination, ECG, 2D echocardiogram, hemogram, ionogram, liver and kidney function. 24-hour and 5-day evaluations: symptoms, physical examination, recording of medical therapy and previous 24-hour urinary output, ECG, hemogram, ionogram, liver and kidney function, and evaluation of arrhythmic episodes and heart rate and blood pressure trends in previous 24 hours. 3- and 6-month evaluations: number of hospital admissions and length of hospital stay due to HF, and mortality. 3. Evaluation of primary endpoint. EFFECTIVENESS: assessed by a clinical score including 2 subjective parameters (1. NYHA functional class, 2. patient self-evaluation symptom class) and 6 objective parameters (3. body weight, 4. pulmonary congestion, 5. previous 24-hour diuresis, 6. serum creatinine, 7. oral HF medication, 8. intravenous HF medication). Definition of clinical effectiveness: improvement in > or = 1 subjective parameters plus improvement in > or = 1 objective parameters, with all other parameters unchanged. SAFETY: The therapy was judged safe in the absence of any serious adverse event with a probable or undetermined causal relationship with levosimendan. Primary endpoint evaluation: Patients reached the primary endpoint when levosimendan was both effective and safe according to the above definitions.