Bio-Humoral and Non-Invasive Haemodynamic Correlates of Renal Venous Flow Patterns across the Heart Failure Spectrum.

Background: We evaluated the bio-humoral and non-invasive haemodynamic correlates of renal congestion evaluated by Doppler renal venous flow (RVF) across the heart failure (HF) spectrum, from asymptomatic subjects with cardiovascular risk factors (Stage A) and structural heart disease (Stage B) to patients with clinically overt HF (Stage C). Methods: Ultrasound evaluation, including echocardiography, lung ultrasound and RVF, along with blood and urine sampling, was performed in 304 patients. Results: Continuous RVF was observed in 230 patients (76%), while discontinuous RVF (dRVF) was observed in 74 (24%): 39 patients had pulsatile RVF, 18 had biphasic RVF and 17 had monophasic RVF. Stage C HF was significantly more common among patients with dRVF. Monophasic RVF was associated with worse renal function and a higher urinary albumin-to-creatinine ratio (uACR). After adjusting for hypertension, diabetes mellitus, the presence of Stage C HF and serum creatinine levels, worsening RVF patterns were associated with higher NT-proBNP levels, worse right ventricular-arterial coupling, larger inferior vena cava and higher echo-derived pulmonary artery wedge pressure. This trend was confirmed when only patients with HF Stage C were analysed after adjusting for the left ventricle ejection fraction (LVEF). Conclusion: Abnormal RVF is common across the HF spectrum. Worsening RVF patterns are independently associated with increased congestion, worse non-invasive haemodynamics and impaired RV-arterial coupling. RVF evaluation could refine prognostic stratification across the HF spectrum, irrespective of LVEF.

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.

Left Ventricular Mass and Thickness: Why Does It Matter?

Several left ventricular geometric patterns have been described both in healthy and pathologic hearts. Left ventricular mass, wall thickness, and the ratio of wall thickness to radius are important measures to characterize the spectrum of left ventricular geometry. For clinicians, an increase in left ventricular mass is the hallmark of left ventricular hypertrophy. Although pathologic hypertrophy initially can be compensatory, eventually it may become maladaptive and evolve toward progressive left ventricular dysfunction and heart failure. In particular, patients who show left ventricular dilation and hypertrophy in association with a low relative wall thickness are likely to carry the highest risk.

Prevalence and determinants of left ventricular diastolic dysfunction in obese subjects and the role of left ventricular global longitudinal strain and mass normalized to height.

BACKGROUND: Left ventricular (LV) diastolic dysfunction (DD) is a frequent finding in obesity and may predispose to the development of heart failure (HF). However, no data are available on the prevalence of DD after the introduction of the 2016 Recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. METHODS AND RESULTS: To assess the impact of the new Recommendations on the prevalence of DD and on their clinical and echocardiographic correlates in obesity, a prospective study was performed in 588 subjects with an ejection fraction (EF) ≥50% and no history of HF either obese (n = 402; mean age: 47 ± 12 years; women 71%; body mass index [BMI]: 44 ± 8 kg/m2 ), overweight (n = 86; BMI: 28 ± 1 kg/m2 ), or with a normal weight (n = 100; BMI: 22 ± 2 kg/m2 ). All subjects underwent an echocardiographic and Doppler study, including the assessment of global longitudinal strain (GLS). DD occurred in 19% of obese patients, 12% of overweight subjects, and 2% of normal weight subjects. We used multivariable logistic analysis to assess the risk of DD. In patients with BMI ≥30 kg/m2 , LV mass normalized to height (2.7) (OR: 1.04, P = .0028), and GLS (OR: 0.85, P = .0032) were associated with an increased risk of DD followed by EF (OR: 0.91, P = .045), diabetes (OR: 1.91, P = .065), and systolic blood pressure (OR: 1.02, P = .076). CONCLUSION: These results show that DD is highly prevalent among obese subjects and impairment of longitudinal systolic mechanics, as reflected by GLS reduction, and LV mass normalized to height are major independent predictors of DD in this patients' population.

Combining cardiopulmonary exercise testing with echocardiography: a multiparametric approach to the cardiovascular and cardiopulmonary systems.

Exercise intolerance is a prominent feature of several cardiovascular conditions. However, the physical effort requires the intertwined adaptation of several factors, namely the cardiovascular system, the lungs, and peripheral muscles. Several abnormalities in each domain may be present in a given patient. Cardiopulmonary exercise testing (CPET) has been used to investigate metabolic and ventilatory alterations responsible for exercise intolerance but does not allow for direct evaluation of cardiovascular function. However, this can readily be obtained by concomitant exercise-stress echocardiography (ESE). The combined CPET-ESE approach allows for precise and thorough phenotyping of the pathophysiologic mechanisms underpinning exercise intolerance. Thus, it can be used to refine the diagnostic workup of patients with dyspnoea of unknown origin, as well as improve risk stratification and potentially guide the therapeutic approach in specific conditions, including left and right heart failure or valvular heart disease. However, given its hitherto sporadic use, both the conceptual and technical aspects of CPET-ESE are often poorly known by the clinician. Improving knowledge in this field could significantly aid in anticipating individual disease trajectories and tailoring treatment strategies accordingly. Therefore, we designed this review to revise the pathophysiologic correlates of exercise intolerance, the practical principles of the combined CPET-ESE examination, and its main applications according to current literature.

Detecting the vulnerable carotid plaque: the Carotid Artery Multimodality imaging Prognostic study design.

BACKGROUND: Carotid artery disease is highly prevalent and a main cause of ischemic stroke and vascular dementia. There is a paucity of information on predictors of serious vascular events. Besides percentage diameter stenosis, international guidelines also recommend the evaluation of qualitative characteristics of carotid artery disease as a guide to treatment, but with no agreement on which qualitative features to assess. This inadequate knowledge leads to a poor ability to identify patients at risk, dispersion of medical resources, and unproven use of expensive and resource-consuming techniques, such as magnetic resonance imaging, positron emission tomography, and computed tomography. OBJECTIVES: The Carotid Artery Multimodality imaging Prognostic (CAMP) study will: prospectively determine the best predictors of silent and overt ischemic stroke and vascular dementia in patients with asymptomatic subcritical carotid artery disease by identifying the noninvasive diagnostic features of the 'vulnerable carotid plaque'; assess whether 'smart' use of low-cost diagnostic methods such as ultrasound-based evaluations may yield at least the same level of prospective information as more expensive techniques. STUDY DESIGN: We will compare the prognostic/predictive value of all proposed techniques with regard to silent or clinically manifest ischemic stroke and vascular dementia. The study will include ≥300 patients with asymptomatic, unilateral, intermediate degree (40-60% diameter) common or internal carotid artery stenosis detected at carotid ultrasound, with a 2-year follow-up. The study design has been registered on Clinicaltrial.gov on December 17, 2020 (ID number NCT04679727).

Global longitudinal strain in heart failure with reduced ejection fraction: Prognostic relevance across disease severity as assessed by automated cluster analysis.

BACKGROUND: Ejection fraction (EF) is still widely used to categorize heart failure (HF) patients but has limitations. Global longitudinal strain (GLS) has emerged as a new prognosticator in HF, independent of EF. AIM: We investigated the incremental predictive benefit of GLS over different risk profiles as identified by automated cluster analysis of simple echocardiographic parameters. METHODS AND RESULTS: In 797 HFrEF patients (age 66 ± 12y; mean EF 30 ± 7%), unsupervised cluster analysis of 10 routine echocardiographic variables (without GLS) was performed. Median follow-up was 37 months. End-point was all-cause mortality. Association between risk profiles, GLS, and mortality was assessed by Cox proportional-hazard modeling with interaction term. Cluster analysis allocated patients to 3 different risk phenogroups (PG): PG-1 (mild diastolic dysfunction [DD], moderate systolic dysfunction, no pulmonary hypertension, normal right ventricular [RV] function); PG-2 (moderate DD, mild pulmonary hypertension, normal RV function); PG-3 (severe DD, advanced systolic dysfunction, pulmonary hypertension, RV dysfunction). Compared to PG-1, PG-2 and PG-3 showed increased adjusted-hazard ratio (1.71; 95% CI:1.05-2.77, P = 0.30; and 2.58; 95% CI:1.50-4.44, P < 0.001, respectively). GLS was independently associated with outcome in the whole population (adjusted-HR: 1.11; 95% CI: 1.05-1.17, P = 0.001); however, profile membership modified the relationship between GLS and outcome which was no longer significant in PG-3 (P for interaction = 0.003). CONCLUSIONS: Within HFrEF populations, clustering of routine echocardiography parameters can automatically identify patients with different risk profiles; further assessment by GLS may be useful for patients with not advanced disease.

Effects of sacubitril/valsartan on B-type natriuretic peptide circulating levels and loop diuretic dose in a case series of stabilized heart failure patients with left ventricular ejection fraction ≤35.

Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor, was shown to improve outcome in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). There are reasons for believing that the concept that the lower the B-type natriuretic peptide (BNP) circulating level the better the prognosis may no longer be correct in patients treated with sacubitril/valsartan, since sacubitril may interfere with BNP clearance. We reported a case series of ten patients with stable chronic HF and LVEF ≤35% (mean age: 64 ± 8 years; 30% female), referred to our outpatient HF clinic, treated with sacubitril/valsartan, in whom the global amelioration of NYHA class and LVEF was coupled with a clinically significant decrease in BNP levels and a reduction of loop diuretic dose. Average sacubitril/valsartan daily dose was 220 mg. The median duration of treatment was 15 months (range: 6-21 months). Seventy percent of patients exhibited an improvement in exercise tolerance, as indicated by the change in NYHA class. There was also an improvement in LVEF from 28 ± 5% to 39 ± 7%. Clinically significant reductions in BNP levels were evident, with a median change from 181 pg/ml to 70 pg/ml. Furosemide daily dose decreased from a median of 43.3 mg to 12.5 mg. This case series suggests that BNP may still be valuable for the assessment of ambulatory HF patients, after the optimization of sacubitril/valsartan therapy.

The Added Value of Exercise Stress Echocardiography in Patients With Heart Failure.

Doppler echocardiography can provide reliable and repeatable measures of cardiac index (CI), whereas lung ultrasound (LUS) represents a quantitative approach to assess pulmonary congestion. We tested the hypothesis that simultaneous assessment of CI and LUS during exercise stress echocardiography (ESE) may define heart failure (HF) outpatients with different risk of adverse outcome. Standard transthoracic echocardiography and LUS (B-lines) evaluation were assessed during semisupine ESE. CI and B-lines were measured at baseline and peak exercise. Resting plasma B-type natriuretic peptide levels were also evaluated. We enrolled 105 HF patients (87 males; age 62 ± 11 years; New York Heart Association class I to III) with reduced left ventricular ejection fraction (30 ± 7%). Patients were classified into 4 profiles: (1) peak CI ≥4.0 l/min/m2 and peak B-lines <15 (no evidence of congestion or hypoperfusion, n = 47); (2) peak CI ≥4.0 l/min/m2 and peak B-lines ≥15 (congestion with adequate perfusion, n = 23); (3) peak CI <4.0 l/min/m2 and peak B-lines <15 (hypoperfusion without congestion, n = 13); and (4) peak CI <4.0 l/min/m2 and peak B-lines ≥15 (congestion and hypoperfusion, n = 22). There were 21 cardiovascular deaths and 18 hospitalizations for worsening HF during a median follow-up of 29 months. Multivariate predictors of the combined end point were peak hemodynamic profiles (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.19 to 2.21; p = 0.002), B-type natriuretic peptide (HR 1.00, 95% CI 1.00 to 1.01; p = 0.001), and rest E/e' (HR 1.09, 95% CI 1.03 to 1.15; p = 0.002). Survival analysis showed a worse survival in patients with ESE-derived D profile, followed by patients with C, B, and A profile (log-rank: chi-square = 40.5; p <0.0001). In conclusion, dual evaluation of CI and LUS during ESE is useful for risk stratification of HF patients with reduced ejection fraction. Evidence of pulmonary congestion and low CI at peak ESE identifies a subgroup with a very high risk of adverse outcome.

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.

Echo- and B-Type Natriuretic Peptide-Guided Follow-Up versus Symptom-Guided Follow-Up: Comparison of the Outcome in Ambulatory Heart Failure Patients.

Recent European Society of Cardiology and American Heart Association/American College of Cardiology Guidelines did not recommend biomarker-guided therapy in the management of heart failure (HF) patients. Combination of echo- and B-type natriuretic peptide (BNP) may be an alternative approach in guiding ambulatory HF management. Our aim was to determine whether a therapy guided by echo markers of left ventricular filling pressure (LVFP), lung ultrasound (LUS) assessment of B-lines, and BNP improves outcomes of HF patients. Consecutive outpatients with LV ejection fraction (EF) ≤ 50% have been prospectively enrolled. In Group I (n=224), follow-up was guided by echo and BNP with the goal of achieving E-wave deceleration time (EDT) ≥ 150 ms, tissue Doppler index E/e' < 13, B-line numbers < 15, and BNP ≤ 125 pg/ml or decrease >30%; in Group II (n=293), follow-up was clinically guided, while the remaining 277 patients (Group III) did not receive any dedicated follow-up. At 60 months, survival was 88% in Group I compared to 75% in Group II and 54% in Group III (χ 2 53.5; p < 0.0001). Survival curves exhibited statistically significant differences using Mantel-Cox analysis. The number needed to treat to spare one death was 7.9 (Group I versus Group II) and 3.8 (Group I versus Group III). At multivariate Cox regression analyses, major predictors of all-cause mortality were follow-up E/e' (HR: 1.05; p=0.0038) and BNP >125 pg/ml or decrease ≤30% (HR: 4.90; p=0.0054), while BNP > 125 pg/ml or decrease ≤30% and B-line numbers ≥15 were associated with the combined end point of death and HF hospitalization. Evidence-based HF treatment guided by serum biomarkers and ultrasound with the goal of reducing elevated BNP and LVFP, and resolving pulmonary congestion was associated with better clinical outcomes and can be valuable in guiding ambulatory HF management.

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.

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].

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.