Estimation of increased pulmonary wedge pressure by an algorithm based on noninvasively measured pulmonary diastolic pressure in cardiac patients independent of left ventricular ejection fraction.

AIM: Pulmonary artery diastolic pressure (PADP) correlates closely with pulmonary wedge pressure (PAWP); therefore, we sought to evaluate whether an algorithm based on PADP assessment by the Doppler pulmonary regurgitation (PR) end-diastolic gradient (PRG) may aid in estimating increased PAWP in cardiac patients with reduced or preserved left ventricular (LV) ejection fraction (EF). METHODS AND RESULTS: Right heart catheterization, with estimation of PAWP, right atrial pressure (RAP), PADP, and Doppler echocardiography, was carried out in 183 patients with coronary artery disease (n = 63), dilated cardiomyopathy (n = 52), or aortic stenosis (n = 68). One-hundred and seventeen patients had LV EF <50%. We measured the pressure gradients across the tricuspid and pulmonary valves from tricuspid regurgitation (TRV) and PR velocities. Doppler-estimated PADP (e-PADP) was obtained by adding the estimated RAP to PRG. An algorithm based on e-PADP to predict PAWP, that included TRV, left atrial volume index, and mitral E/A, was developed and validated in derivation (n = 90) and validation (n = 93) subgroups. Both invasive PADP (r = .92, P < .001) and e-PADP (r = .72, P < .001) correlated closely with PAWP, and e-PADP predicted PAWP (AUC: 0.85, CI: 0.79-0.91) with a 94% positive predictive value (PPV) and a 55% negative predictive value (NPV), after exclusion of five patients with precapillary pulmonary hypertension. The e-PADP-based algorithm predicted PAWP with higher accuracy (PPV = 94%; NPV = 67%; accuracy = 85%; kappa: 0.65, P < .001) than the ASE-EACVI 2016 recommendations (PPV = 97%; NPV = 47%; accuracy = 68% undetermined = 18.9%; kappa: 0.15, P < .001). CONCLUSIONS: An algorithm based on noninvasively e-PADP can accurately predict increased PAWP in patients with cardiac disease and reduced or preserved LV EF.

Similar predictive value of six-minute walking distance and B-type natriuretic peptide in heart failure with reduced to mid-range ejection fraction.

The prognostic insights of heart failure (HF) with mid-range (40-49%) ejection fraction (HFmrEF) are not fully elucidated. We investigated whether the six-minutes walking test (6MWT) and brain natriuretic peptide (BNP) are predictive of outcome across the spectrum of LV systolic dysfunction and whether the HFmrEF cut-off impacts the risk stratification abilities of these tests. We studied 538 outpatients, aged 70±12 years, 28% females, with stable chronic HF and EF<50%, 349 with HFmrEF and 189 with HFrEF. End-points were all-cause and cardiac death. HFrEF patients were more often male, with ischemic etiology, severe symptoms, higher BNP levels, and cardiac mortality than HFmrEF subjects. During 32 (15-46) months follow-up, 123 (23%) patients died, 95 (18%) for cardiac causes. Cut-offs of 125 pg/ml for BNP and 360 meters for 6MWT distance were associated with lower all-cause (10% vs 38%, p<0.001 and 10% vs 26%, p<0.001, respectively) and cardiac mortality (6% vs 36%, p<0.001 and 8% vs 23%, p<0.001, respectively). BNP (HR 2.144, 95%CI, 1.403-3.276) and 6MWT walked distance (HR 1.923, 95%CI, 1.195-3.096) independently predicted outcome, after adjustment for age, gender, obesity, kidney dysfunction, ischemic etiology, NYHA class, unlike the 40% LVEF threshold. Model discrimination and survival differences were significant across LVEF strata. Higher BNP levels and shorter walked distance combined identified patients (26% overall) at particularly poor prognosis in both phenotype groups. Despite differences between HFmrEF and HFrEF patients in clinical and biomarker profile, BNP levels and 6MWT walked distance retain prognostic value over the entire spectrum of LV systolic dysfunction.

Echo-derived peak cardiac power output-to-left ventricular mass with cardiopulmonary exercise testing predicts outcome in patients with heart failure and depressed systolic function.

AIMS: Peak cardiac power output-to-mass (CPOM) represents a measure of the rate at which cardiac work is delivered respect to the potential energy stored in left ventricular (LV) mass. We studied the value of CPOM and cardiopulmonary exercise test (CPET) in risk stratification of patients with heart failure (HF). MATERIALS AND RESULTS: We studied 159 patients with chronic HF (mean rest LV ejection fraction 30%) undergoing CPET and exercise stress echocardiography. CPOM was calculated as the product of a constant (K = 2.22 × 10-1) with cardiac output (CO) and the mean blood pressure (MBP), divided by LV mass (M), and expressed in the unit of W/100 g: CPOM = [K × CO (L/min) × MBP (mmHg)]/LVM(g). Patients were followed-up for the primary endpoint, including all-cause death, ventricular assist device implantation, and heart transplantation, and the secondary endpoint that comprised hospitalization for HF. In multivariate Cox regression analyses, peak CPOM was selected as the most powerful independent predictor of both primary and secondary endpoint [hazard ratio (HR) 0.004, 95% confidence interval (CI) 0.004-0.3; P = 0.002 and HR 0.09, 95% CI 0.02-0.55; P = 0.009]. Sixty-month survival free from the combined endpoint was 85% in those exhibiting oxygen consumption (VO2) > 14 mL/min/kg and peak CPOM > 0.6 W/100 g. Peak VO2 ≤ 14 mL/min/kg provided incremental prognostic value over demographic and clinical variables, brain natriuretic peptide, and resting echocardiographic parameters (χ2 from 58 to 64; P = 0.04), that was further increased by peak CPOM ≤ 0.6 W/100 g (χ2 77; P < 0.001). CONCLUSION: Peak CPOM and peak VO2 showed independent and incremental prognostic values in patients with chronic HF.

Prognostic value of cardiac power output to left ventricular mass in patients with left ventricular dysfunction and dobutamine stress echo negative by wall motion criteria.

AIMS: Cardiac power output to left ventricular mass (power/mass) is an index of myocardial efficiency reflecting the rate at which cardiac work is delivered with respect to the potential energy stored in the left ventricular mass. In the present study, we sought to investigate the capability of power/mass assessed at peak of dobutamine stress echocardiography to predict mortality in patients with ischaemic cardiomyopathy and no inducible ischaemia. METHODS AND RESULTS: One-hundred eleven patients (95 males; age 68 ± 10 years) with 35 ± 7% mean left ventricular ejection fraction and a dobutamine stress echocardiography (up to 40 µg/kg/min) negative by wall motion criteria formed the study population. Power/mass at peak stress was obtained as the product of a constant (K = 2.22 × 10-1) with cardiac output and the mean arterial pressure divided by left ventricular mass to convert the units to W/100 g. Patients were followed up for a median of 29 months (inter-quartile range 16-72 months). All-cause mortality was the only accepted clinical end point. Mean peak-stress power/mass was 0.70 ± 0.31 W/100 g. During follow-up, 29 deaths (26%) were registered. With a receiver operating characteristic analysis, a peak-stress power/mass ≤0.50 W/100 g [area under curve 0.72 (95% CI 0.63; 0.80), sensitivity 59%, specificity 80%] was the best value for predicting mortality. Univariate prognostic indicators were age, male sex, peak-stress ejection fraction, peak-stress stroke volume, peak-stress cardiac output, peak-stress cardiac power output ≤1.48 W, and peak-stress power/mass ≤0.50 W/100 g. At multivariate analysis, age (HR 1.08, 95% CI 1.04; 1.14; P = 0.004) and peak-stress power/mass ≤0.50 W/100 g (HR 4.05, 95% CI 1.36; 12.00; P = 0.01) provided independent prognostic information. Three-year mortality was 14% in patients with peak-stress power/mass >0.50 W/100 g and 47% in those with peak-stress power/mass ≤0.50 W/100 g (log-rank 20.4; P < 0.0001). CONCLUSION: Power/mass assessed at peak of dobutamine stress echocardiography allows effective prognostication in patients with ischaemic cardiomyopathy and test result negative by wall motion criteria. In particular, a peak-stress power/mass ≤50 W/100 g is a strong and multivariable predictor of mortality.

Echo and BNP serial assessment in ambulatory heart failure care: Data on loop diuretic use and renal function.

We compared the follow-up data on loop diuretic use and renal function, as assessed by serum creatinine levels, and the estimated glomerular filtration rate (eGFR), of two groups of consecutive ambulatory HF patients: 1) the clinically-guided group, in which management was clinically driven based on the institutional protocol of the HF Unit of the Cardiovascular and Thoracic Department of Pisa (standard of care) and 2) the echo and B-type natriuretic peptide (BNP) guided group (patients conforming to the protocol of the Network Labs Ultrasound (NEBULA) in HF Study Group: Pisa, Perugia, Pavia; Verona, Auckland, and Veruno), in which therapy was delivered according to the serial assessment of BNP and echocardiography. Patients whose follow-up was based on standard of care had a significant higher prevalence of worsening renal function, that was likely related to higher diuretic dosages, whilst, a better management of renal function was observed in the echo-BNP-guided group. The data is related to "Echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: An observational study of 1137 outpatients" (A. Simioniuc, E. Carluccio, S. Ghio, A. Rossi, P. Biagioli, G. Reboldi, G.G. Galeotti, F. Lu, C. Zara, G. Whalley, P.G. Temporelli, F.L. Dini, 2016; K.J. Harjai, H.K. Dinshaw, E. Nunez, M. Shah, H. Thompson, T. Turgut, H.O. Ventura, 1999; A. Ahmed, A. Husain, T.E. Love, G. Gambassi, L.J. Dell׳Italia, G.S. Francis, M. Gheorghiade, R.M. Allman, S. Meleth, R.C. Bourge, 2006) [1], [2], [3].

Echo and natriuretic peptide guided therapy improves outcome and reduces worsening renal function in systolic heart failure: An observational study of 1137 outpatients.

BACKGROUND: B-type natriuretic peptide (BNP) and echocardiography are potentially useful adjunct to guide management of patients with chronic heart failure (HF).Thus, the aim of this retrospective, multicenter study was to compare outcomes and renal function in outpatients with chronic HF with reduced ejection fraction (HFrEF) who underwent an echo and BNP guided or a clinically driven protocol for follow-up. METHODS AND RESULTS: In 1137 consecutive outpatients, management was guided according to echo-Doppler signs of elevated left ventricular filling pressure and BNP levels conforming to the protocol of the Network Labs Ultrasound (NEBULA) in HF Study Group in 570 (mean EF=30%), while management was clinically driven based on the institutional protocol of the HF Unit of the Cardiovascular and Thoracic Department in 567 (mean EF=33%). Propensity score, matching several confounding baseline variables, was used to match pairs based on treatment strategy. The median follow-up was 37.4months. After propensity matching, a lower incidence of death (HR 0.45, 95%CI: 0.30-0.67, p<0.0001), and death or worsening renal function (HR 0.49, 95%CI 0.36-0.67, p<0.0001) was apparent in echo-BNP-guided group compared to clinically-guided group. Worsening of renal function (≥0.3mg/dl increase in serum creatinine) was observed in 9.8% of echo-BNP-guided group and in 21.4% of clinical assessed group (p<0.0001). The daily dose of loop diuretics did not change in echo-BNP-guided group, while it increased in 65% of patients in clinically-guided group (p<0.0001). CONCLUSIONS: Echo and BNP guided management may improve the outcome and reduce worsening of renal function in outpatients with chronic HFrEF.

Right ventricular recovery during follow-up is associated with improved survival in patients with chronic heart failure with reduced ejection fraction.

AIMS: A compromised tricuspid annular plane systolic excursion (TAPSE) is associated with worse survival in patients with chronic heart failure with reduced ejection fraction (HFrEF). However, it is not known whether a reversible abnormal TAPSE at follow-up predicts survival. Our aim was to evaluate whether a reversible abnormal TAPSE is associated with a better survival in patients with chronic HFrEF. METHODS AND RESULTS: A complete echocardiography was performed in 706 patients with chronic HFrEF (LVEF ≤45%) at baseline and after 6 ± 3 months. Right ventricular (RV) systolic function was evaluated using TAPSE. The study endpoint was all-cause mortality. At baseline, TAPSE was severely reduced (≤14 mm) in 89 (13%) patients, and slightly reduced (>14 but <18 mm) in 157 (22%) patients. During a median follow-up of 40 months, 152 patients reached the endpoint. The event rate (per 100 patients/year) was lower in patients with persistently normal TAPSE (≥18 mm, n = 393) [3.3%, 95% confidence interval (CI) 2.5-4.3], and in those with reversible TAPSE (n = 120) (4.6%, 95% CI 3.1-7.0), compared with patients with worsening TAPSE (n = 90) (11.9%, 95% CI 8.7-16.3), and those with persistently reduced TAPSE (n = 103) (12.6%, 95% CI 9.3-17.1; log-rank 69.4, P < 0.0001). A reversible abnormal TAPSE was associated with improved survival at multivariable Cox regression analysis (hazard ratio 0.48, 95% CI 0.29-0.79, P = 0.004). CONCLUSIONS: Patients with chronic HFrEF who have abnormal TAPSE at baseline but reverse their dysfunction during follow-up have better survival than patients with either worsened TAPSE or persistently abnormal TAPSE, and similar to that of patients with persistently normal TAPSE.

[Clinical scores in chronic heart failure: does an ideal score exist?]. / Gli score clinici nell'insufficienza cardiaca cronica: esiste uno score ideale?

Numerous prognostic markers have shown to be predictive of patient outcome in heart failure (HF). The recent guidelines of the European Society of Cardiology for the diagnosis and treatment of acute and chronic HF have identified as many as 57 individual markers in patients with HF, including demographic data, etiology, comorbidities, clinical, radiological, hemodynamic, echocardiographic and biochemical parameters. If more accurate risk stratification is required, several scoring systems have been proposed. This article reviews scoring systems for HF prognostication. Although most of the models include readily available clinical information, usually NYHA functional class, left ventricular ejection fraction (LVEF) and comorbidities, quite a few of them comprise Doppler echocardiographic variables, other than LVEF, and circulating levels of natriuretic peptides. In order to achieve a better prediction of the outcome, an ideal score should be based on a comprehensive Doppler echocardiographic examination, the assessment of circulating biomarkers, and a more objective evaluation of exercise tolerance.

The potential value of integrated natriuretic peptide and echo-guided heart failure management.

There is increasing interest in guiding Heart Failure (HF) therapy with Brain Natriuretic Peptide (BNP) or N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP), with the goal of lowering concentrations of these markers (and maintaining their suppression) as part of the therapeutic approach in HF. However, recent European Society of Cardiology (ESC) and American Heart Association/ American College of Cardiology (AHA/ACC) guidelines did not recommend biomarker-guided therapy in the management of HF patients. This has likely to do with the conceptual, methodological, and practical limitations of the Natriuretic Peptides (NP)-based approach, including biological variability, slow time-course, poor specificity, cost and venipuncture, as well as to the lack of conclusive scientific evidence after 15 years of intensive scientific work and industry investment in the field. An increase in NP can be associated with accumulation of extra-vascular lung water, which is a sign of impending acute heart failure. If this is the case, an higher dose of loop diuretics will improve symptoms. However, if no lung congestion is present, diuretics will show no benefit and even harm. It is only a combined clinical, bio-humoral (for instance with evaluation of renal function) and echocardiographic assessment which may unmask the pathophysiological (and possibly therapeutic) heterogeneity underlying the same clinical and NP picture. Increase in B-lines will trigger increase of loop diuretics (or dialysis); the marked increase in mitral insufficiency (at baseline or during exercise) will lead to increase in vasodilators and to consider mitral valve repair; the presence of substantial inotropic reserve during stress will give a substantially higher chance of benefit to beta-blocker or Cardiac Resynchronization Therapy (CRT). To each patient its own therapy, not with a "blind date" with symptoms and NP and carpet bombing with drugs, but with an open-eye targeted approach on the mechanism predominant in that individual patient. A monocular, specialistic, unidimensional approach to HF can miss its pathogenetic and clinical complexity, which only can be overcome with an integrated, versatile and tailored approach.

A multiparametric clinical and echocardiographic score to risk stratify patients with chronic systolic heart failure: derivation and testing.

Although echo Doppler and biomarkers are the most common examinations performed worldwide in heart failure (HF), they are rarely considered in risk scores. In outpatients with chronic HF and left ventricular ejection fraction (LVEF) ≤45%, data on clinical status, echo Doppler variables, aminoterminal pro-type B natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), and drug therapies were combined to build up a multiparametric score. We randomly selected 250 patients to produce a derivation cohort and 388 patients were used as a testing cohort. Follow-up lasted 29 ± 23 months. The univariable predictors that entered into the multivariable Cox model were as follows: furosemide daily dose >25 mg, inability to tolerate angiotensin converting enzyme (ACE) inhibitors, inability to tolerate ß-blockers, age >75 years, New York Heart Association (NYHA) >2, eGFR<60 mL/min, NT-proBNP plasma levels above the median, tricuspid plane systolic excursion (TAPSE) ≤14 mm, LV end-diastolic volume index (LVEDVi) >96 mL/m(2) , moderate-to-severe mitral regurgitation (MR) and LVEF <30%. The scores of prognostic factors were obtained with the respective odds ratio divided by the lower odd ratio: 4 points for furosemide dose, 3 points for age, NT-proBNP, LVEDVi, TAPSE, 2 points for inability to tolerate ß-blockers, inability to tolerate ACE inhibitors, NYHA, eGFR<60 mL/min, moderate-to-severe MR, 1 point for LVEF. The multiparametric score predicted all-cause mortality either in the derivation cohort (68.4% sensitivity, 79.5% specificity, area under the curve [AUC] 78.7%) or in the testing cohort (73.7% sensitivity, 71.3% specificity, AUC 77.2%). All-cause mortality significantly increased with increasing score both in the derivation and in the testing cohort (P < 0.0001). In conclusion, this multiparametric score is able to predict mortality in chronic systolic HF.

The 'Echo Heart Failure Score': an echocardiographic risk prediction score of mortality in systolic heart failure.

AIMS: Although many transthoracic echocardiographic (TTE) measurements have been shown to predict outcome in heart failure (HF), whether incremental risk prediction is afforded by their combination is unknown. We developed a simple echocardiographic risk score of mortality in HF patients. METHODS AND RESULTS: We performed TTE in 747 systolic HF patients followed-up for 34 ± 23 months. The Cox hazard model was used to evaluate the association between 14 TTE parameters and death. The Echo Heart Failure Score (EHFS) was derived by assigning the value of 1 to each independent predictor when present, and 0 when it was absent, and then by summing the number. The 3-year risk prediction improvement was tested by adding the EHFS to a model containing clinical predictors, and by calculating the C index and net reclassification improvement (NRI). Five baseline TTE variables (end-systolic volume index, left atrial volume index, mitral E-wave deceleration time, tricuspid annular peak systolic excursion, and pulmonary artery systolic pressure) remained independent predictors of mortality. The mortality rate (per 100 patients/year) significantly increased with EHFS ranging from 0 to 5 (EHFS = 0, 2.7%; 1, 5.2%; 2, 10.1%; 3, 13.7%, 4, 29.7%; 5, 36.9%; P < 0.0001). Patients with EHFS ≥3 had a mortality hazard ratio of 3.58 (95% confidence interval 2.74-4.78) compared with EHFS <3. Adding EHFS to the base model improved the C index (from 0.74 to 0.81, P < 0.0001), yielding a continuous NRI of 0.63 (P < 0.0001). CONCLUSIONS: The EHFS, an easily obtainable echo score, improved risk prediction of death over traditional prognostic factors in systolic HF patients, and it may prove useful for risk stratification.

Prognostic relevance of a non-invasive evaluation of right ventricular function and pulmonary artery pressure in patients with chronic heart failure.

AIM: To determine the prognostic relevance of the echocardiographic evaluation of pulmonary artery systolic pressure (PASP) and tricuspid annular plane systolic excursion (TAPSE) in patients with chronic heart failure (CHF). Pulmonary hypertension (PH) and right ventricular (RV) dysfunction have both been associated with poor prognosis in CHF. METHODS AND RESULTS: A complete echocardiographic examination was performed in 658 outpatients with CHF and LVEF <45%. PASP was available in 544 (83%) patients, TAPSE in all patients, and E wave deceleration time (DT) in 643 (98%) patients. During a median follow-up period of 38 months, 125 patients died, 5 underwent urgent heart transplantation, and 5 had an appropriately detected and treated episode of ventricular fibrillation. At Cox survival analysis (composite endpoint was death, urgent heart transplantation, and ventricular fibrillation), patients with PASP ≥40 mmHg plus TAPSE ≤14 mm had a poorer prognosis than those with high PASP but preserved TAPSE; RV dysfunction associated with normal PASP did not carry additional risks. Similar results were obtained when patients were grouped on the basis of DT (restrictive vs. non restrictive) and TAPSE. CONCLUSIONS: A simple echocardiographic evaluation of PASP and RV function with TAPSE may improve risk stratification in patients with CHF. Importantly, if PASP cannot be recorded at echocardiography, a restrictive DT, measurable in the vast majority of patients, may be coupled with TAPSE to stratify patients.

Independent and incremental value of severely enlarged left atrium in risk stratification of very elderly patients with chronic systolic heart failure.

The authors sought to assess the impact on survival of demographic, clinical, and echo-Doppler parameters in patients with chronic heart failure due to left ventricular systolic dysfunction divided according to age groups. This study included 734 patients (age 69±11 years) who were classified into tertiles of age: I (22-66 years), II (67-76 years), and III (77-94 years). Severely enlarged left atrial size was defined as ≥52 mm in men and ≥47 mm in women. Multivariable analysis identified male sex (P=.018) and severely enlarged left atrium (P=.024) as significant correlates of all-cause mortality in the very elderly cohort, while restrictive filling pattern (RFP) (P=.004) and New York Heart Association class III or IV (P=.005) among patients of the first tertile and RFP (P=.028) among patients in the second tertile were independently associated with mortality after 30±21 months of follow-up. At the interactive stepwise model in the very elderly population, a severely enlarged left atrium, added to the model after clinical parameters and ejection fraction, moved the chi-square value from 20.7 to 25.8 (P=.048). RFP emerged as the single best predictor of all-cause mortality in the younger and intermediate ranges, whereas severely enlarged left atrium was the best predictor in the very elderly.

Association of furosemide dose with clinical status, left ventricular dysfunction, natriuretic peptides, and outcome in clinically stable patients with chronic systolic heart failure.

In chronic heart failure (HF), high daily doses of furosemide have been associated with increased mortality. The authors sought to evaluate the relationships between orally administered furosemide doses, clinical status, left ventricular (LV) dysfunction, N-terminal proBNP (NT-proBNP), and outcome in 400 outpatients with chronic HF and LV ejection fraction (EF) ≤ 45%. Clinical status, NT-proBNP levels, and estimated glomerular filtration rate (eGFR) were evaluated. Median follow-up duration was 32 months. The median values of daily-dose furosemide and of furosemide dose normalized to body surface area were 25 mg (12.5-62.5 mg) and 15 mg/m(2) (13-34 mg/m(2)), respectively. A total of 32% of patients had decompensated HF according to Framingham score and criteria for congestion. In clinically stable patients, a multivariable Cox model, which included clinical and echocardiographic parameters plus NT-proBNP, hemoglobin, and eGFR, showed that normalized furosemide dose (P=.017), anemia (P=.060), age (P=.080), and New York Heart Association class (P=.080) were predictors of all cause-mortality. In patients with decompensated HF, LV end-systolic volume index (P=.018), NT-proBNP (P=.060), and reduced eGFR (P=.070) were independently related to the outcome. Normalized furosemide dose was a major determinant of prognosis in patients with chronic HF but without ongoing signs and symptoms, and this suggests a possible negative interaction of this drug in clinically stable patients.

Right ventricular dysfunction is associated with chronic kidney disease and predicts survival in patients with chronic systolic heart failure.

AIMS: Chronic kidney disease (CKD) and right ventricular (RV) dysfunction are important predictors of prognosis in heart failure (HF). We investigated the relationship between RV dysfunction and CKD in outpatients with chronic systolic HF, an association which remains poorly defined. METHODS AND RESULTS: Outpatients (n = 373) with chronic HF and left ventricular ejection fraction (LVEF) ≤45% underwent clinical and echo-Doppler evaluations and were followed up for 31 ± 24 months. Tricuspid annular plane systolic excursion (TAPSE) assessed RV dysfunction. The estimated glomerular filtration rate (GFR) was measured by the simplified Modification of Diet in Renal Disease (MDRD) formula. Correlation analysis was used to characterize the association between TAPSE and estimated GFR. Odds ratios (ORs) for CKD and hazard ratios (HRs) for all-cause mortality were assessed using multivariable logistic or proportional hazards regression models. TAPSE and estimated GFR were significantly correlated (r = 0.38, P < 0.0001). TAPSE ≤14 mm was associated with elevated estimated right atrial pressure and N-terminal pro brain natriuretic peptide levels. TAPSE ≤14 mm increased the odds of estimated GFR <60 mL/min/1.73 m(2), OR [95% confidence interval (CI)] = 2.51(1.44-4.39), P < 0.0001 and predicted all-cause mortality, HR (95% CI) = 1.80 (1.20-2.71) after multivariable adjustment. CONCLUSIONS: Right ventricular dysfunction is cross-sectionally associated with CKD and prospectively predicts survival in outpatients with chronic systolic HF. These data suggest RV dysfunction to be one of the possible mechanistic links between HF and CKD.

Prognostic value of pulsed tissue Doppler imaging for the assessment of left ventricular systolic function in patients with nonischemic dilated cardiomyopathy.

There is still some debate regarding the prognostic significance of left ventricular longitudinal systolic dysfunction as assessed by tissue Doppler (TD) imaging in patients with chronic heart failure (HF), since previous studies have included patients with postischemic wall motion abnormalities. Thus, this study was designed to ascertain whether TD-derived longitudinal systolic dysfunction may influence the outcome of patients with nonischemic chronic HF. In 200 consecutive patients with chronic HF secondary to dilated cardiomyopathy and no history of ischemic heart disease, peak systolic mitral annular velocity (S(m) ) was measured by pulsed TD at the septal and lateral annular sites. The end points were cardiac death or hospitalization for worsening HF. Mean follow-up duration was 30 months. In a time independent analysis, averaged S(m) calculated as the average of septal and lateral S(m) , resulted to be a significant predictor of outcome in the study population (area under receiver-operator characteristic curve: cardiovascular death, 0.69, P < 0.0001; cardiovascular events, 0.64, P = 0.0005). In a time-dependent analysis, average S(m) was associated with both cardiovascular death (hazard ratio 0.832, P = 0.0019) and cardiovascular events (hazard ratio 0.904, P = 0.039), independently of other clinical risk factors and echocardiographic parameters of systolic function. Septal S(m) but not lateral S(m) was independently associated with the outcome measures. In conclusion, the assessment of systolic mitral annular velocity by pulsed TD is a useful indicator for prognostic stratification of patients with nonischemic dilated cardiomyopathy and chronic HF.

Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy.

BACKGROUND: Functional mitral regurgitation (FMR) is a common finding in patients with heart failure (HF), but its effect on outcome is still uncertain, mainly because in previous studies sample sizes were relatively small and semiquantitative methods for FMR grading were used. OBJECTIVE: To evaluate the prognostic value of FMR in patients with HF. METHODS AND RESULTS: Patients with HF due to ischaemic and non-ischaemic dilated cardiomyopathy (DCM) were retrospectively recruited. The clinical end point was a composite of all-cause mortality and hospitalisation for worsening HF. FMR was quantitatively determined by measuring vena contracta (VC) or effective regurgitant orifice (ERO) or regurgitant volume (RV). Severe FMR was defined as ERO >0.2 cm(2) or RV >30 ml or VC >0.4 cm. Restrictive mitral filling pattern (RMP) was defined as E-wave deceleration time <140 ms. The study population comprised 1256 patients (mean age 67 ± 11; 78% male) with HF due to DCM: 27% had no FMR, 49% mild to moderate FMR and 24% severe FMR. There was a powerful association between severe FMR and prognosis (HR = 2.0, 95% CI 1.5 to 2.6; p<0.0001) after adjustment of left ventricular ejection fraction and RMP. The independent association of severe FMR with prognosis was confirmed in patients with ischaemic DCM (HR = 2.0, 95% CI 1.4 to 2.7; p<0.0001) and non-ischaemic DCM (HR = 1.9, 95% CI 1.3 to 2.9; p = 0.002). CONCLUSION: In a large patient population it was shown that a quantitatively defined FMR was strongly associated with the outcome of patients with HF, independently of LV function.

Patterns of left ventricular remodeling in chronic heart failure: prevalence and prognostic implications.

BACKGROUND AND AIM: Many descriptors of left ventricular (LV) remodeling have important prognostic implications in patients with chronic systolic heart failure (HF). We sought to assess the prognostic value of the combination of increased LV mass with a disproportion between wall thickness and internal diameter. METHODS AND PATIENTS: Patients (n = 536) with chronic HF, ejection fraction <50% and LV end-diastolic volume index >91 mL/m(2), classified according to LV mass index and relative wall thickness (RWT), were followed up for 33 ± 21 months. Ventricular mass was determined using a standard M-mode echocardiographic method. Relative wall thickness was defined as the ratio of (sum of interventricular septum thickness in diastole + posterior wall thickness in diastole)/LV end-diastolic diameter. RESULTS: Prevalence of the pattern of increased LV mass index, defined as LV mass index >148 g/m(2) in men and >122 g/m(2) in women, and decreased RWT (<0.34) was 29%. Multivariable predictors of all-cause mortality were age >70 years (P < .0001), New York Heart Association class >2 (P < .0001), increased LV mass index, and decreased RWT (P = .003), E wave deceleration time ≤140 ms (P = .005), and male gender (P = .025). Patients with increased LV mass index and decreased RWT had a worse survival (33%) than patients with less LV mass index and normal to reduced RWT (log-rank 23.92; P < .0001). Comparisons of Cox models showed that the combination of increased mass index and decreased RWT added prognostic value to a model that included ejection fraction and end-systolic volume index. CONCLUSION: In patients with systolic HF, an independent and incremental risk of adverse outcome was associated with increased mass index and decreased RWT.

Adenosine receptor mRNA expression in normal and failing minipig hearts.

Chronic heart failure (HF) is associated with increased systemic (plasma) and reduced local (myocardial) adenosine levels. The final biological action of adenosine in a particular organ or cell population may depend on the relative degree of expression and signaling efficiency of individual adenosine receptor (AR) subtypes. The aim of this study was to determine the myocardial expression of ARs, in the different chambers of failing versus normal minipig hearts. Cardiac tissue was collected from minipigs without (n = 5) and with HF (n = 5). ARs, adenosine deaminase, and tumor necrosis factor-α (TNF-α) mRNA expression were evaluated by real time-polymerase chain reaction. ARs were expressed in all cardiac regions. After 3 weeks of pacing, the only significant change was observed in A2BR mRNA expression in the left ventricle (P = 0.02), with a similar trend for A3R, A2AR, and A1R. A trend toward higher expression of mRNA adenosine deaminase in the myocardium of pigs with HF was observed. TNF-α mRNA expression was higher after HF in all cardiac chambers (left ventricle: P = 0.009), and a significant correlation was observed between TNF-α and A2BR (r = 0.80, P < 0.0001). In this study, A2BR mRNA resulted in being overexpressed in the left ventricle of pigs with HF as well as TNF-α expression possibly testifying a link between AR expression, inflammation, and HF.

Placental stem cells pre-treated with a hyaluronan mixed ester of butyric and retinoic acid to cure infarcted pig hearts: a multimodal study.

AIMS: Pre-treating placenta-derived human mesenchymal stem cells (FMhMSCs) with a hyaluronan mixed ester of butyric and retinoic acid (HBR) potentiates their reparative capacity in rodent hearts. Our aim was to test FMhMSCs in a large-animal model by employing a novel combination of in vivo and ex vivo analyses. METHODS AND RESULTS: Matched regional quantifications of myocardial function and viability were performed by magnetic resonance imaging (MRI) and positron emission tomography (PET) 4 weeks after myocardial infarction combined with intramyocardial injection of FMhMSCs (n = 7), or HBR-pre-treated FMhMSCs (HBR-FMhMSCs, n = 6), or saline solution (PBS, n = 7). Sham-operated pigs (n = 4) were used as control animals. Despite no differences in the ejection fraction and haemodynamics, regional MRI revealed, in pigs treated with HBR-FMhMSCs compared with the other infarcted groups, a 40% smaller infarct scar size and a significant improvement of the end-systolic wall thickening and circumferential shortening of the infarct border zone. Consistently, PET showed that myocardial perfusion and glucose uptake were, respectively, 35 and 23% higher in the border zone of pigs treated with HBR-FMhMSCs compared with the other infarcted groups. Histology supported in vivo imaging; the delivery of HBR-FMhMSCs significantly enhanced capillary density and decreased fibrous tissue by approximately 68%. Moreover, proteomic analysis of the border zone in the HBR-FMhMSCs group and the FMhMSCs group indicated, respectively, 45 and 30% phenotypic homology with healthy tissue, while this homology was only 26% in the border zone of the PBS group. CONCLUSION: Our results support a more pronounced reparative potential of HBR-pre-treated FMhMSCs in a clinically relevant animal model of infarction and highlight the necessity of using combined diagnostic imaging to avoid underestimations of stem cell therapeutic effects in the heart.