Patient phenotype profiling using echocardiography and natriuretic peptides to personalise heart failure therapy.

Heart failure (HF) is a progressive condition with a clinical picture resulting from reduced cardiac output (CO) and/or elevated left ventricular (LV) filling pressures (LVFP). The original Diamond-Forrester classification, based on haemodynamic data reflecting CO and pulmonary congestion, was introduced to grade severity, manage, and risk stratify advanced HF patients, providing evidence that survival progressively worsened for those classified as warm/dry, cold/dry, warm/wet, and cold/wet. Invasive haemodynamic evaluation in critically ill patients has been replaced by non-invasive haemodynamic phenotype profiling using echocardiography. Decreased CO is not infrequent among ambulatory HF patients with reduced ejection fraction, ranging from 23 to 45%. The Diamond-Forrester classification may be used in combination with the evaluation of natriuretic peptides (NPs) in ambulatory HF patients to pursue the goal of early identification of those at high risk of adverse events and personalise therapy to antagonise neurohormonal systems, reduce congestion, and preserve tissue/renal perfusion. The most benefit of the Guideline-directed medical treatment is to be expected in stable patients with the warm/dry profile, who more often respond with LV reverse remodelling, while more selective individualised treatments guided by echocardiography and NPs are necessary for patients with persisting congestion and/or tissue/renal hypoperfusion (cold/dry, warm/wet, and cold/wet phenotypes) to achieve stabilization and to avoid further neurohormonal activation, as a result of inappropriate use of vasodilating or negative chronotropic drugs, thus pursuing the therapeutic objectives. Therefore, tracking the haemodynamic status over time by clinical, imaging, and laboratory indicators helps implement therapy by individualising drug regimens and interventions according to patients' phenotypes even in an ambulatory setting.

Effect of sacubitril/valsartan on cardiac remodeling compared with other renin-angiotensin system inhibitors: a difference-in-difference analysis of propensity-score matched samples.

BACKGROUND: In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin-angiotensin system (RAS) inhibitors is not well known. METHODS: HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8-12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. RESULTS: After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m2, P = 0.0005; + 4.68 mL/m2, P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient's age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). CONCLUSION: In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors.

Cardiometabolic Phenotyping in Heart Failure: Differences between Patients with Reduced vs. Preserved Ejection Fraction.

AIMS: We explored multiple cardiometabolic patterns, including inflammatory and congestive pathways, in patients with heart failure (HF). METHODS AND RESULTS: We enrolled 270 HF patients with reduced (<50%, HFrEF; n = 96) and preserved (≥50%, HFpEF; n = 174) ejection fraction. In HFpEF, glycated hemoglobin (Hb1Ac) seemed to be relevant in its relationship with inflammation as Hb1Ac positively correlated with high-sensitivity C-reactive protein (hs-CRP; Spearman's rank correlation coefficient ρ = 0.180, p < 0.05). In HFrEF, we found a correlation between Hb1Ac and norepinephrine (ρ = 0.207, p < 0.05). In HFpEF, we found a positive correlation between Hb1Ac and congestion expressed as pulmonary B lines (ρ = 0.187, p < 0.05); the inverse correlation, although not significant, was found in HFrEF between Hb1Ac and N-terminal pro-B-type natriuretic peptide (ρ = 0.079) and between Hb1Ac and B lines (ρ = -0.051). In HFrEF, we found a positive correlation between E/e' ratio and Hb1Ac (ρ = 0.203, p < 0.05) and a negative correlation between tricuspid annular systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (sPAP) (TAPSE/sPAP ratio) (ρ = -0.205, p < 0.05) and Hb1Ac. In HFpEF, we found a negative correlation between TAPSE/sPAP ratio and uric acid (ρ = -0.216, p < 0.05). CONCLUSION: In HF patients, HFpEF and HFrEF phenotypes are characterized by different cardiometabolic indices related to distinct inflammatory and congestive pathways. Patients with HFpEF showed an important relationship between inflammatory and cardiometabolic parameters. Conversely, in HFrEF, there is a significant relationship between congestion and inflammation, while cardiometabolism appears not to influence inflammation, instead affecting sympathetic hyperactivation.

Innovations in medical therapy of heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) is a pathological condition still characterized by high rates of mortality and disease exacerbation frequently leading to hospitalization, thus there is a continuous need for pharmacological treatments impacting on disease stability and long-term prognosis. Moreover, the phenotype of heart failure patients is continuously changing over time, and the development of new heart failure drugs is crucial to promote a personalized and targeted approach. In recent years, several therapeutic innovations have emerged in the landscape of acute and chronic HFrEF, largely changing and improving our approach to the disease. Various studies on new drugs and experimental therapeutic approaches are ongoing. The present review discusses the latest data on both recently approved drugs and developing therapeutic targets, in order to provide a critical overview for an informed and optimal approach to such a complex disease.

Right ventricular failure in left heart disease: from pathophysiology to clinical manifestations and prognosis.

Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis.

Acute pericarditis in patients receiving coronavirus disease 2019 vaccines: a case series from the community.

BACKGROUND: International agencies reported that cases of pericarditis occur very rarely following the administration of coronavirus disease 2019 (COVID-19) vaccines. Herewith, we described a series of patients from the community diagnosed with acute pericarditis after vaccination. METHODS: We retrospectively included 28 patients (median age 51 years, 79% female) with or without a positive history of acute respiratory syndrome coronavirus 2 recovered infection who were diagnosed with acute pericarditis following the administration of COVID-19 vaccine. We excluded specific identifiable causes of pericarditis, including infectious, autoimmune, neoplastic and metabolic disease. Patients were referred for a complete cardiovascular evaluation. Transthoracic echocardiography (TTE) was performed and diagnosis of acute pericarditis was achieved according to current guidelines. RESULTS: There were 16 patients administered with Pfizer-BioNTech/Comirnaty vaccine, 8 with Moderna/Spikevax vaccine and 4 with Astra Zeneca/Vaxzevria vaccine. Nine patients had been previously diagnosed with COVID-19, while the others had no prior history of COVID-19. Eleven patients had no comorbidity while the others had between one and four comorbidities. Ten patients had a history of rheumatic or autoimmune diseases. Chest pain was present in 24 patients. Minor ECG abnormalities were detected in 10 patients, T-wave inversion in 6, and 7 patients had concave ST elevation. The majority of patients showed mild pericardial effusions at TTE. Only two patients exhibited large pericardial effusions. CONCLUSION: This case series shows a higher incidence of acute pericarditis in patients administered with COVID-19 vaccines than previously estimated, probably because of a more comprehensive assessment of clinical as well as echocardiographic parameters.

Diabetes Is the Strongest Predictor of Limited Exercise Capacity in Chronic Heart Failure and Preserved Ejection Fraction (HFpEF).

Background and Aim: Type 2 diabetes mellitus (T2DM) is a known risk factor in patients with heart failure (HF), but its impact on phenotypic presentations remains unclear. This study aimed to prospectively examine the relationship between T2DM and functional exercise capacity, assessed by the 6-min walk test (6-MWT) in chronic HF. Methods: We studied 344 chronic patients with HF (mean age 61 ± 10 years, 54% female) in whom clinical, biochemical, and anthropometric data were available and all patients underwent an echo-Doppler study and a 6-MWT on the same day. The 6-MWT distance divided the cohort into; Group I: those who managed ≤ 300 m and Group II: those who managed >300 m. Additionally, left ventricular (LV) ejection fraction (EF), estimated using the modified Simpson's method, classified patients into HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF). Results: The results showed that 111/344 (32%) patients had T2DM, who had a higher prevalence of arterial hypertension (p = 0.004), higher waist/hips ratio (p = 0.041), higher creatinine (p = 0.008) and urea (p = 0.003), lower hemoglobin (p = 0.001), and they achieved shorter 6-MWT distance (p < 0.001) compared with those with no T2DM. Patients with limited exercise (<300 m) had higher prevalence of T2DM (p < 0.001), arterial hypertension (p = 0.004), and atrial fibrillation (p = 0.001), higher waist/hips ratio (p = 0.041), higher glucose level (p < 0.001), lower hemoglobin (p < 0.001), larger left atrium (LA) (p = 0.002), lower lateral mitral annular plane systolic excursion (MAPSE) (p = 0.032), septal MAPSE (p < 0.001), and tricuspid annular plane systolic excursion (TAPSE) (p < 0.001), compared with those performing >300 m. In the cohort as a whole, multivariate analysis, T2DM (p < 0.001), low hemoglobin (p = 0.008), atrial fibrillation (p = 0.014), and reduced septal MAPSE (p = 0.021) independently predicted the limited 6-MWT distance.In patients with HFpEF, diabetes [6.083 (2.613-14.160), p < 0.001], atrial fibrillation [6.092 (1.769-20.979), p = 0.002], and septal MAPSE [0.063 (0.027-0.184), p = 0.002], independently predicted the reduced 6-MWT, whereas hemoglobin [0.786 (0.624-0.998), p = 0.049] and TAPSE [0.462 (0.214-0.988), p = 0.041] predicted it in patients with HFrEF. Conclusion: Predictors of exercise intolerance in patients with chronic HF differ according to LV systolic function, demonstrated as EF. T2DM seems the most powerful predictor of limited exercise capacity in patients with HFpEF.

Exercise-induced pulmonary hypertension in HFpEF and HFrEF: Different pathophysiologic mechanism behind similar functional impairment.

AIMS: Pathophysiological mechanisms behind cardio-pulmonary impairment in heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction are likely different. We analysed them using combined cardiopulmonary-exercise stress echocardiography (CPET-ESE). METHODS: We matched 1:1 subjects with HFrEF (n = 90) and HFpEF (n = 90) for age, sex, body mass index (BMI), peak oxygen consumption, and minute ventilation/carbon dioxide production slope. All patients underwent a symptom-limited graded ramp bicycle CPET-ESE compared with 40 age-, sex- and BMI-matched healthy controls. RESULTS: During a median follow-up of 25 months, we observed 22 deaths and 80 HF hospitalisations, with similar distribution between HFpEF and HFrEF. Compared with HFrEF, HFpEF had a higher prevalence of metabolic syndrome (p = 0.02) with higher levels of high-sensitivity C-reactive protein and uric acid (p < 0.01). The multipoint mean pulmonary artery pressure/cardiac output (mPAP/CO) slope showed equally increased values in HFrEF and HFpEF (3.5 ± 1.8 and 3.7 ± 1.5 mmHg/L/min) compared with controls (1.8 ± 1.1 mmHg/L/min; p < 0.0001). During exercise, HFpEF displayed more adverse interaction of right ventricle-pulmonary artery (RV-PA; tricuspid annular plane systolic excursion/systolic pulmonary artery pressure: 0.40 ± 0.2 vs 0.47 ± 0.2 mm/mmHg in HFrEF; p < 0.01) and left atrium-left ventricle (LA-LV; LA reservoir strain/LV global longitudinal strain: 1.5 ± 0.8 vs 2.2 ± 1.1 in HFrEF; p < 0.01). The latter were independent predictors of mPAP/CO slope, along with hs-CRP (adjusted R2: 0.21; p < 0.0001). CONCLUSION: Despite similar disease severity, HFpEF and HFrEF show different pathophysiological mechanisms. HFpEF is characterised by a worse LA-LV and RV-PA interaction than HFrEF, with more prevalent low-grade systemic inflammation. In HFpEF, these features may have a role in exercise-induced pulmonary hypertension.

Echocardiographically defined haemodynamic categorization predicts prognosis in ambulatory heart failure patients treated with sacubitril/valsartan.

AIM: Echo-derived haemodynamic classification, based on forward-flow and left ventricular (LV) filling pressure (LVFP) correlates, has been proposed to phenotype patients with heart failure and reduced ejection fraction (HFrEF). To assess the prognostic relevance of baseline echocardiographically defined haemodynamic profile in ambulatory HFrEF patients before starting sacubitril/valsartan. METHODS AND RESULTS: In our multicentre, open-label study, HFrEF outpatients were classified into 4 groups according to the combination of forward flow (cardiac index; CI:< or ≥2.0 L/min/m2 ) and early transmitral Doppler velocity/early diastolic annular velocity ratio (E/e': ≥ or <15): Profile-A: normal-flow, normal-pressure; Profile-B: low-flow, normal-pressure; Profile-C: normal-flow, high-pressure; Profile-D: low-flow, high-pressure. Patients were started on sacubitril/valsartan and followed-up for 12.3 months (median). Rates of the composite of death/HF-hospitalization were assessed by multivariable Cox proportional-hazards models. Twelve sites enrolled 727 patients (64 ± 12 year old; LVEF: 29.8 ± 6.2%). Profile-D had more comorbidities and worse renal and LV function. Target dose of sacubitril/valsartan (97/103 mg BID) was more likely reached in Profile-A (34%) than other profiles (B: 32%, C: 24%, D: 28%, P < 0.001). Event-rate (per 100 patients per year) progressively increased from Profile-A to Profile-D (12.0%, 16.4%, 22.9%, and 35.2%, respectively, P < 0.0001). By covariate-adjusted Cox model, profiles with low forward-flow (B and D) remained associated with poor outcome (P < 0.01). Adding this categorization to MAGGIC-score and natriuretic peptides, provided significant continuous net reclassification improvement (0.329; P < 0.001). Intermediate and high-dose sacubitril/valsartan reduced the event's risk independently of haemodynamic profile. CONCLUSIONS: Echocardiographically-derived haemodynamic classification identifies ambulatory HFrEF patients with different risk profiles. In real-world HFrEF outpatients, sacubitril/valsartan is effective in improving outcome across different haemodynamic profiles.

Benefit from sacubitril/valsartan is associated with hemodynamic improvement in heart failure with reduced ejection fraction: An echocardiographic study.

BACKGROUND: Sacubitril/valsartan improves outcome in patients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF, HFrEF). However, little is known about possible mechanisms underlying this favourable effect. PURPOSE: To assess changes in echocardiographically-derived hemodynamic profiles induced by sacubitril/valsartan and their impact on outcome. METHODS: In this multicenter, open-label study, 727 HFrEF outpatients underwent comprehensive echocardiography at baseline (before starting sacubitril/valsartan) and after 12 months. Estimated LV filling pressure (E/e') and cardiac index (CI, l/min/m2) were combined to determine 4 hemodynamic profiles: profile-A (normal-flow/normal-pressure); profile-B (low-flow/normal-pressure); profile-C: (normal-flow/high-pressure); profile-D: (low-flow/high-pressure). Changes among categories were recorded, and their associations with rates of the composite of death/HF-hospitalization were assessed by multivariable Cox analysis. RESULTS: At baseline, 29% had profile-A, 15% had profile-B, 32% profile-C, and 24% profile-D. After 12 months, the hemodynamic profile improved in 53% of patients (all profile-A achievers, or profile-D patients achieving either C or B profile), while it remained unchanged in 39% patients and worsened in 9%. Prevalence of improved profile progressively increased with increasing dose of sacubitril/valsartan (P < 0.0001). After the second echocardiography, patients were followed up 12.6 ± 7.6 months: event-rate was lower in patients with improved profile (12.3%, 95%CI: 9.4-16.1) compared to patients in whom hemodynamic profile remained unchanged (29.9%, 24.0-37.3) or worsened (31.2%, 20.7-46.9, P < 0.0001). Improved hemodynamic profile was associated with favourable outcome independent of LVEF and other covariates (HR 0.65, 95%CI: 0.45-0.95, P < 0.05). CONCLUSION: In HFrEF patients, the beneficial prognostic effects of sacubitril/valsartan are associated with improvement in hemodynamic conditions.

Left atrial structural and mechanical remodelling in heart failure with reduced ejection fraction.

AIMS: In patients with heart failure with reduced ejection fraction (HFrEF), an association between left atrial (LA) dilatation and dysfunction is expected, but the degree of coexistence of the two abnormalities and their relative prognostic role is not known. METHODS AND RESULTS: A total of 626 HFrEF patients formed the study population. All of them underwent a comprehensive echocardiographic evaluation. LA maximal volume was indexed to body surface area (LAVi); LA function was assessed using strain analysis during the reservoir phase: peak atrial longitudinal strain (PALS) analysis. Study primary endpoint was overall mortality or hospitalization for worsening heart failure. Four groups of patients were included in this study according to LAVi (≤34 or >34 mL/m2 ) and PALS (≤23% or >23%); 61 (10%) patients had normal LA volume and function (Group 1), 58 (9%) had LA dilatation but normal function (Group 2), 100 (16%) had normal volume but abnormal function (Group 3), and 407 (65%) had enlarged left atrium and abnormal function (Group 4). PALS was associated with primary endpoint in patients with both normal-size [Groups 1 and 3: hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.88-0.96; P = 0.0006] and dilated left atria (Groups 2 and 4: HR 0.93, 95% CI 0.91-0.96; P < 0.0001). In contrast, LAVi was associated with the primary endpoint in patients with abnormal LA function (Groups 3 and 4: HR 1.018, 95% CI 1.011-1.024; P < 0.00001) but not in those with normal PALS (Groups 1 and 2: HR 1.023, 95% CI 0.99-1.057; P = 0.1). CONCLUSIONS: Left atrial dilatation and dysfunction frequently but not invariably coexist. PALS emerged as a significant prognostic parameter in HFrEF even in the absence of LA dilation.

Predicting the transition to and progression of heart failure with preserved ejection fraction: a weighted risk score using bio-humoural, cardiopulmonary, and echocardiographic stress testing.

AIMS: Risk stratification of heart failure (HF) patients with preserved ejection fraction (HFpEF) can promote a more personalized treatment. We tested the prognostic value of a multi-parametric evaluation, including biomarkers, cardiopulmonary exercise testing-exercise stress echocardiography (CPET-ESE), and lung ultrasound, in HFpEF patients and subjects at risk of developing HF (HF Stages A and B). BACKGROUND: Risk stratification of heart failure (HF) patients with preserved ejection fraction (HFpEF) can promote a more personalized treatment. DESIGN: We tested the prognostic value of a multi-parametric evaluation, including biomarkers, cardiopulmonary exercise testing-exercise stress echocardiography (CPET-ESE), and lung ultrasound, in HFpEF patients and subjects at risk of developing HF (HF Stages A and B). METHODS AND RESULTS: We performed a resting clinical/bio-humoural evaluation and a symptom-limited CPET-ESE in 274 patients (45 Stage A, 68 Stage B, and 161 Stage C-HFpEF) and 30 age- and sex-matched healthy controls. During a median follow-up of 18.5 months, we reported 71 HF hospitalizations and 10 cardiovascular deaths. Cox proportional-hazards regression identified five independent predictors and each was assigned a number of points proportional to its regression coefficient: stress-rest ΔB-lines >10 (3 points), peak oxygen consumption <16 mL/kg/min (2 points), minute ventilation/carbon dioxide production slope ≥36 (2 points), peak systolic pulmonary artery pressure ≥50 mmHg (1 point) and resting N-terminal pro-brain natriuretic peptide (NT-proBNP) >900 pg/mL (1 point). The event-free survival probability for low risk (<3 points), intermediate risk (3-6 points), and high risk (>6 points) were 93%, 52%, and 20%, respectively. The area under the curve (AUC) for the scoring system to predict events was 0.92 (95% CI 0.88-0.96), with an accuracy significantly higher than the individual components of the score (all P < 0.01 vs. individual AUCs). CONCLUSION: A weighted risk score including NT-proBNP, markers of cardiopulmonary dysfunction and indices of exercise-induced pulmonary congestion identifies HFpEF patients at increased risk for adverse events and Stage A and B subjects more likely to progress towards more advanced HF stages.

Cardiac Reserve and Exercise Capacity: Insights from Combined Cardiopulmonary and Exercise Echocardiography Stress Testing.

BACKGROUND: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak oxygen consumption (VO2) noninvasively. To improve the analysis of the mechanisms behind effort intolerance, we examined whether exercise stress echocardiography measurements relate to directly measured peak VO2 during exercise in a large cohort of patients within the heart failure (HF) spectrum. METHODS: We performed a symptom-limited graded ramp bicycle CPET exercise stress echocardiography in 30 healthy controls and 357 patients: 113 at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 244 in HF stage C with preserved (HFpEF, n = 101) or reduced ejection fraction (HFrEF, n = 143). RESULTS: Peak VO2 significantly decreased from controls (23, 21.7-29.7 mL/kg/minute; median, interquartile range) to stage A-B (18, 15.4-20.7 mL/kg/minute) and stage C (HFpEF: 13.6, 11.8-16.8 mL/kg/minute; HFrEF: 14.2, 10.7-17.5 mL/kg/minute). A regression model to predict peak VO2 revealed that peak left ventricular (LV) systolic annulus tissue velocity (S'), peak tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (right ventricle-pulmonary artery coupling), and low-load left atrial (LA) reservoir strain/E/e' (LA compliance) were independent predictors, in addition to peak heart rate, stroke volume, and workload (adjusted R2 = 0.76, P < .0001). The model was successfully tested in subjects with atrial fibrillation (n = 49) and with (n = 224) and without (n = 163) beta-blockers (all P < .01). Peak S' showed the highest accuracy in predicting peak VO2 < 10 mL/kg/minute (cut point ≤ 7.5 cm/sec, area under the curve = 0.92, P < .0001) and peak VO2 > 20 mL/kg/minute (cut point > 12.5 cm/sec, area under the curve = 0.84, P < .0001) in comparison with the other cardiac variables of the model (P < .05). CONCLUSIONS: Peak VO2 is directly related to measures of LV systolic function, LA compliance, and right ventricle-pulmonary artery coupling, in addition to heart rate and stroke volume and independently of workload, age, and sex. The evaluation of cardiac mechanics may provide more insights into the causes of effort intolerance in subjects from HF stages A-C.

Left atrial stiffness predicts cardiac events in patients with heart failure and reduced ejection fraction: The impact of diabetes.

BACKGROUND: The aim of this study was to investigate the relationship between diabetes mellitus (DM) and left atrial (LA) remodelling in a group of patients with heart failure and reduced ejection fraction (HFrEF), and their combined impact on cardiac events (CE). METHODS: This study included 136 consecutive HFrEF patients (65 ± 11 years), 36 had DM, and 86 had increased LA stiffness (LASt). All patients underwent complete conventional and tissue Doppler echocardiographic measurements were made including LA volumes and function. LASt was calculated using the formula: LASt = E/e' ratio / PALS. RESULTS: At 55 ± 37 months follow-up, free survival from CE was 69% in patients without DM and 44.4% in those with DM (p < .0001). The CE free survival was lower in patients with increased LASt compared to normal LASt, (50 versus. 80%, p < .001), irrespective of the presence of DM (27 versus. 71%, p < .001).The best cut-off value of LASt for predicting CE in the group as a whole was ≥ 0.82% [81% sensitivity, 72% specificity and AUC 0.82 (p < .001)]. LASt ≥ 0.82% also predicted CE in no DM patients [78% sensitivity, 71% specificity and AUC 0.80 (p < .001)] and was a stronger predictor in DM patients [85% sensitivity, 71% specificity and AUC = 0.847 (p < .001)]. CONCLUSION: High LA stiffness is associated with poor clinical outcome in patients with HFrEF. Diabetes has an additional incremental value in determining clinical outcome in those patients.

Pre-existing type 2 diabetes is associated with increased all-cause death independently of echocardiographic predictors of poor prognosis only in ischemic heart disease.

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

Persistent congestion, renal dysfunction and inflammatory cytokines in acute heart failure: a prognosis study.

AIMS: Chronic kidney dysfunction (CKD) and persistent congestion influence heart failure prognosis, but little is known about the role of inflammation in this association. We assessed the relationship between inflammatory biomarkers, persistent congestion and CKD and their prognostic implications in patients with acute heart failure. METHODS: We enrolled 97 hospitalised patients (mean age: 66 ±â€Š12 years, ejection fraction: 30 ±â€Š8%) with acute heart failure. Before discharge, congestion was assessed using a heart failure scoring system on the basis of Framingham criteria. Circulating levels of high-sensitivity C-reactive protein, TGF-ß-1, IL-1, IL-6, IL-10, TNF-α, soluble tumour necrosis factor receptor type 1 and 2 were measured. Patients were divided into four groups according to the presence of CKD (estimated glomerular filtration rate <60 ml/min/1.73 m) and congestion (Framingham heart failure score ≥2). The primary end point was the combination of death and rehospitalisation for acute heart failure. RESULTS: During a median follow-up of 32 months, 37 patients died and 14 were rehospitalised for acute heart failure. Patients with CKD and congestion had significantly higher TNF-α (P = 0.037), soluble tumour necrosis factor receptor type 1 (P = 0.0042) and soluble tumour necrosis factor receptor type 2 (P = 0.001), lower TGF-ß-1 (P = 0.02) levels, and the worst outcome (P < 0.0001). Congestion (P = 0.01) and CKD (P = 0.02) were independent predictors of the end-point together with N-terminal prohormone of brain natriuretic peptide (P = 0.002) and TNF-α (P = 0.004). TNF-α attenuated the direct relation between CKD, congestion and outcome, explaining 40% of the difference in the outcome. CONCLUSION: In patients hospitalised with acute heart failure, the prognostic impact of persistent congestion and CKD is associated with increased cytokine levels, which may also interfere with the outcome.

Speckle Tracking-Derived Left Atrial Stiffness Predicts Clinical Outcome in Heart Failure Patients with Reduced to Mid-Range Ejection Fraction.

BACKGROUND AND AIM: Left atrial stiffness (LASt) is an important marker of cardiac function, especially in patients with heart failure (HF); it explains symptoms on the basis of pressure transfer to the pulmonary circulation. The aim of this study was to evaluate the relationship between LASt and cardiac events (CE) in HF patients with reduced to mid-range ejection fraction. METHODS: The study included 215 consecutive ambulatory HF patients with ejection fraction (EF) < 50% (162 HF reduced EF and 53 HF mid-range EF) of mean age 66 ± 11 years and 24.4% females. Peak LA strain (PALS) was measured by speckle tracking echocardiography and E/e' recorded from the apical four-chamber view. Non-invasive LASt was calculated using the equation: LASt = E/e' ratio/PALS. Documented cardiac events (CE) were HF hospitalization and cardiac death. RESULTS: During a median follow up of 41 ± 34 months, 65 patients (30%) had CE. In multivariate analysis model, only raised LV filling pressure (E/e') (OR = 0.292, (95% CI 0.099 to 0.859), p = 0.02), peak pulmonary artery pressure (PAP) (OR = 1.050 (1.009 to 1.094), p = 0.01), PALS (OR = 0.932 (0.873 to 0.994), p = 0.02) and LASt (OR = 3.781 (1.144 to 5.122), p = 0.001) independently predicted CE. LASt ≥ 0.76% was the most powerful predictor of CE, with 80% sensitivity and 73% specificity (AUC 0.82, CI = 0.73 to 0.87, p < 0.001) followed by PALS ≤ 16%, with 74% sensitivity and 72% specificity (AUC 0.77, CI = 0.71 to 0.84, p < 0.001). These results were consistent irrespective of EF (p < 0.05). CONCLUSION: In this cohort of ambulatory HFrEF and HFmrEF patients, LASt proved the most powerful predictor of clinical outcome.

Haemodynamic and metabolic phenotyping of hypertensive patients with and without heart failure by combining cardiopulmonary and echocardiographic stress test.

AIM: We combined cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE) to identify early haemodynamic and metabolic alterations in patients with hypertension (HT) with and without heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Fifty stable HFpEF-HT outpatients (mean age 68 ± 14 years) on optimal medical therapy, 63 well-controlled HT subjects (mean age 63 ± 11 years) and 32 age and sex-matched healthy controls (mean age 59 ± 15 years) underwent a symptom-limited graded ramp bicycle CPET-ESE. The acquisition protocol included left ventricular cardiac output, global longitudinal strain, E/e', peak oxygen consumption (VO2 ), non-invasive arterial-venous oxygen content difference (AVO2 diff) and lung ultrasound B-lines. There was a decline in peak VO2 from controls (24.4 ± 3 mL/min/kg) to HFpEF-HT (15.2 ± 2 mL/min/kg), passing through HT (18.7 ± 2 mL/min/kg; P < 0.0001). HFpEF-HT displayed a lower peak cardiac output (9.8 ± 0.9 L/min) compared to HT (12.6 ± 1.0 L/min; P = 0.02) and controls (13.3 ± 1.0 L/min; P = 0.01). Peak AVO2 diff was reduced in HFpEF-HT and HT (13.3 ± 2 and 13.5 ± 2 mL/dL vs. controls: 16.9 ± 2 mL/dL; P < 0.0001). A different left ventricular contractility was observed among groups, expressed as low-load global longitudinal strain (-16.8 ± 5% in HFpEF-HT, -18.2 ± 3% in HT, and 20.9 ± 3% in controls; P < 0.0001), and distribution of E/e' and B-lines [HFpEF-HT: 13.7 ± 3 and 16, interquartile range (IQR) 10-22; HT: 9.5 ± 2 and 8, IQR 4-10; controls: 6.2 ± 2 and 0, IQR 0-2; P < 0.0001]. CONCLUSIONS: Reduced peak VO2 values in HT with and without HFpEF may be the result of decreased AVO2 diff. CPET-ESE can also identify mild signs of left ventricular systo-diastolic dysfunction and pulmonary congestion, promoting advances in personalized therapy.

Left atrial compliance index predicts exercise capacity in patients with heart failure and preserved ejection fraction irrespective of right ventricular dysfunction.

BACKGROUND AND AIM: Predictors of exercise capacity in heart failure (HF) with preserved ejection fraction (HFpEF) remain of difficult determination. The aim of this study was to identify predictors of exercise capacity in a group of patients with HFpEF and right ventricle (RV) dysfunction METHODS: In 143 consecutive patients with HFpEF (age 62 ± 9 years, LV EF ≥45) and 41 controls, a complete echocardiographic study was performed. In addition to conventional measurements, LA compliance was calculated using the formula: [LAV max - LAV min/LAV min × 100]. Exercise capacity was assessed using the six-minute walking test (6-MWT). Tricuspid annular plane systolic excursion (TAPSE) < 1.7 cm was utilized to categorize patients with RV dysfunction (n = 40) from those with maintained RV function (n = 103). RESULTS: Patients with RV dysfunction were older (P = 0.002), had higher NYHA class (P = 0.001), higher LV mass index (P = 0.01), reduced septal and lateral MAPSE (all P < 0.001), enlarged LA (P = 0.001) impaired LA compliance index (P < 0.001) and exhibited a more compromised 6-MWT (P = 0.001). LA compliance index correlated more closely with 6-MWT (r = 0.51, P < 0.001) compared with the other LA indices (AP diameter, transverse diameter and volume indexed; r = -0.30, r = -0.35 and r = -0.38, respectively). In multivariate analysis, LA compliance index <60% was 88% sensitive and 61% specific (AUC 0.80, CI = 0.67-0.92 P = 0.001) in predicting exercise capacity. CONCLUSION: An impairment in LA compliance was profound in patients with HFpEF and RV dysfunction and seems to be most powerful independent predictor of limited exercise capacity.

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.