Valutazione della capacità funzionale del paziente con scompenso cardiaco: analisi combinata con test da sforzo cardiopolmonare ed ecocardiografia da stress

Lo scompenso cardiaco (heart failure, HF) è una sindrome clinica complessa derivante dall’insufficienza strutturale o funzionale del riempimento ventricolare e/o dell’eiezione del sangue. La capacità funzionale, caratteristicamente ridotta nello HF, può essere valutata in maniera oggettiva tramite misurazione del consumo di ossigeno (VO2) raggiunto al picco di un esercizio massimale. Il test da sforzo cardiopolmonare rappresenta il gold standard per la valutazione non invasiva del VO2 di picco. Obiettivo di questa tesi è di approfondire i molteplici meccanismi alla base dell’intolleranza allo sforzo. In particolare, è stato ipotizzato che parametri intrinseci della meccanica cardiaca siano predittivi del VO2 di picco, indipendentemente dalle variabili emodinamiche considerate nel principio di Fick (VO2 = frequenza cardiaca x gittata sistolica x differenza artero-venosa di ossigeno) e dal carico di lavoro. Sono stati arruolati 357 pazienti riferiti all’ambulatorio di HF presso l’Azienda Ospedaliera Pisana tra il 2017 e il 2020 e collocabili negli stadi A-C della classificazione American College of Cardiology/American Heart Association dello HF. La popolazione comprendeva 113 soggetti a rischio di sviluppare scompenso cardiaco (classi A-B) e 244 soggetti in classe C, di cui 101 con scompenso a frazione di eiezione ridotta (HFrEF) e 143 con scompenso a frazione di eiezione conservata (HFpEF). I pazienti, così come un gruppo di 30 controlli sani, sono stati sottoposti a test da sforzo cardiopolmonare ed ecocardiografia da stress (CPET-ESE) durante esercizio massimale. VO2 di picco mostrava una riduzione significativa dal gruppo di controllo (mediana: 23 mL/kg/min; scarto interquartile: 21.7–29.7 mL/kg/min) allo stadio A-B (18, 15.4–20.7 mL/kg/min) e C (HFpEF: 13.6, 11.8–16.8 mL/kg/min; HFrEF: 14.2, 10.7–17.5 mL/kg/min). Un modello di regressione multivariata ha evidenziato come la velocità di movimento dell’annulus mitralico in sistole (S’), il rapporto tra l’escursione sistolica del piano anulare della tricuspide e la pressione arteriosa polmonare sistolica (TAPSE/PAPs), il rapporto tra il reservoir strain dell’atrio sinistro ed E/e’, rapporto tra la massima velocità di flusso trans-mitralico durante riempimento ventricolare rapido e la velocità di rilassamento protodiastolico (LA reservoir strain/E/e’) siano, insieme a frequenza cardiaca, gittata sistolica e carico di lavoro, fattori predittivi indipendenti di VO2 di picco (R2 corretto = 0.76, p20 mL/kg/min (cut-point>12.5 cm/s, AUC=0.84, p<0.0001). VO2 di picco appare direttamente correlato a parametri di funzionalità sistolica sinistra (S’), accoppiamento ventricolo destro-circolazione polmonare (TAPSE/PAPs) e compliance atriale sinistra (LA reservoir strain/E/e’), indipendentemente da frequenza cardiaca, gittata sistolica, carico di lavoro, età e sesso. Una valutazione integrata della dinamica cardiocircolatoria potrebbe offrire maggiore comprensione dei meccanismi di riduzione del VO2 in pazienti con HF, con la possibilità di approfondire la fisiopatologia dell’intolleranza allo sforzo e aprire nuove prospettive terapeutiche

Deep phenotype characterization of hypertensive response to exercise: implications on functional capacity and prognosis across the heart failure spectrum

Aims: Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE. Methods and results: We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A-B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36-0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30-0.63) was similar to controls (0.43, 0.35-0.57) but significantly lower than Stages A-B (0.61, 0.47-0.75) and HFpEF (0.63, 0.42-0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF. Conclusion: A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A-B and HFpEF

Haemodynamic forces predicting remodelling and outcome in patients with heart failure treated with sacubitril/valsartan

Abstract Aims A novel tool for the evaluation of left ventricular (LV) systo‐diastolic function through echo‐derived haemodynamic forces (HDFs) has been recently proposed. The present study aimed to assess the predictive value of HDFs on (i) 6 month treatment response to sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) patients and (ii) cardiovascular events. Methods and results Eighty‐nine consecutive HFrEF patients [70% males, 65 ± 9 years, LV ejection fraction (LVEF) 27 ± 7%] initiating sacubitril/valsartan underwent clinical, laboratory, ultrasound and cardiopulmonary exercise testing evaluations. Patients experiencing no adverse events and showing ≥50% reduction in plasma N‐terminal pro‐B‐type natriuretic peptide and/or ≥10% LVEF increase over 6 months were considered responders. Patients were followed up for the composite endpoint of HF‐related hospitalisation, atrial fibrillation and cardiovascular death. Forty‐five (51%) patients were responders. Among baseline variables, only HDF‐derived whole cardiac cycle LV strength (wLVS) was higher in responders (4.4 ± 1.3 vs. 3.6 ± 1.2; p = 0.01). wLVS was also the only independent predictor of sacubitril/valsartan response at multivariable logistic regression analysis [odds ratio 1.36; 95% confidence interval (CI) 1.10–1.67], with good accuracy at receiver operating characteristic (ROC) analysis [optimal cutpoint: ≥3.7%; area under the curve (AUC) = 0.736]. During a 33 month (23–41) median follow‐up, a wLVS increase after 6 months (ΔwLVS) showed a high discrimination ability at time‐dependent ROC analysis (optimal cut‐off: ≥0.5%; AUC = 0.811), stratified prognosis (log‐rank p < 0.0001) and remained an independent predictor for the composite endpoint (hazard ratio 0.76; 95% CI 0.61–0.95; p < 0.01), after adjusting for clinical and instrumental variables. Conclusions HDF analysis predicts sacubitril/valsartan response and might optimise decision‐making in HFrEF patients

Haemodynamic and metabolic phenotyping of patients with aortic stenosis and preserved ejection fraction: A specific phenotype of heart failure with preserved ejection fraction?

AIMS Degenerative aortic valve stenosis with preserved ejection fraction (ASpEF) and heart failure with preserved ejection fraction (HFpEF) display intriguing similarities. This study aimed to provide a non-invasive, comparative analysis of ASpEF versus HFpEF at rest and during exercise. METHODS AND RESULTS We prospectively enrolled 148 patients with HFpEF and 150 patients with degenerative moderate-to-severe ASpEF, together with 66 age- and sex-matched healthy controls. All subjects received a comprehensive evaluation at rest and 351/364 (96%) performed a combined cardiopulmonary exercise stress echocardiography test. Patients with ASpEF eligible for transcatheter aortic valve replacement (n = 125) also performed cardiac computed tomography (CT). HFpEF and ASpEF patients showed similar demographic distribution and biohumoral profiles. Most patients with ASpEF (134/150, 89%) had severe high-gradient aortic stenosis; 6/150 (4%) had normal-flow, low-gradient ASpEF, while 10/150 (7%) had low-flow, low-gradient ASpEF. Both patient groups displayed significantly lower peak oxygen consumption (VO$_{2}$ ), peak cardiac output, and peak arteriovenous oxygen difference compared to controls (all p < 0.01). ASpEF patients showed several extravalvular abnormalities at rest and during exercise, similar to HFpEF (all p < 0.01 vs. controls). Epicardial adipose tissue (EAT) thickness was significantly greater in ASpEF than HFpEF and was inversely correlated with peak VO$_{2}$ in all groups. In ASpEF, EAT was directly related to echocardiography-derived disease severity and CT-derived aortic valve calcium burden. CONCLUSION Functional capacity is similarly impaired in ASpEF and HFpEF due to both peripheral and central components. Further investigation is warranted to determine whether extravalvular alterations may affect disease progression and prognosis in ASpEF even after valve intervention, which could support the concept of ASpEF as a specific sub-phenotype of HFpEF

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 (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 p p p p 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

Impact of epicardial adipose tissue on cardiovascular haemodynamics, metabolic profile, and prognosis in heart failure

AIMS We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary-echocardiography exercise stress. METHODS AND RESULTS We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C-reactive protein in HFrEF, while having a direct association with troponin T and C-reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO$_{2}$ ) and peripheral extraction (AVO$_{2}$ diff), regardless of body mass index. EAT was inversely correlated with peak VO$_{2}$ and AVO$_{2}$ diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow-up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54-0.91). CONCLUSION In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF

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

The incremental value of multi-organ assessment of congestion using ultrasound in outpatients with heart failure

No abstract available

Arterial Hypertension and Cardiopulmonary Function: The Value of a Combined Cardiopulmonary and Echocardiography Stress Test

Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide. Haemodynamic abnormalities, longstanding neurohormonal and inflammatory activation, which are commonly observed in patients with AH, promote cardiac structural remodeling ultimately leading to heart failure (HF) if blood pressure values remain uncontrolled. While several epidemiological studies have confirmed the strong link between AH and HF, the pathophysiological processes underlying this transition remain largely unclear. The combined cardiopulmonary-echocardiography stress test (CPET-ESE) represents a precious non-invasive aid to detect alterations in patients at the earliest stages of HF. The opportunity to study the response of the cardiovascular system to exercise, and to differentiate central from peripheral cardiovascular maladaptations, makes the CPET-ESE an ideal technique to gain insights into the mechanisms involved in the transition from AH to HF, by recognizing alterations that might be silent at rest but influence the response to exercise. Identifications of these subclinical alterations might allow for a better risk stratification in hypertensive patients, facilitating the recognition of those at higher risk of evolution towards established HF. This may also lead to the development of novel preventive strategies and help tailor medical treatment. The purpose of this review is to summarise the potential advantages of using CPET-ESE in the characterisation of hypertensive patients in the cardiovascular continuum

Characterisation of haemodynamic and metabolic abnormalities in the heart failure spectrum: the role of combined cardiopulmonary and exercise echocardiography stress test

Heart failure (HF) is a complex clinical syndrome characterised by different etiologies and a broad spectrum of cardiac structural and functional abnormalities. Current guidelines suggest a classification based on left ventricular ejection fraction (LVEF), distinguishing HF with reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of as a continuous range of conditions, from asymptomatic stages to clinically manifest syndrome. The transition from one stage to the next is associated with a worse prognosis. While the rate of HF-related hospitalisation is similar in HFrEF and HFpEF once clinical manifestations occur, accurate knowledge of the steps and risk factors leading to HF progression is still lacking, especially in HFpEF. Precise hemodynamic and metabolic characterisation of patients with or at risk of HF may help identify different disease trajectories and risk factors, with the potential to identify specific treatment targets that might offset the slippery slope towards overt clinical manifestations. Exercise can unravel early metabolic and haemodynamic alterations that might be silent at rest, potentially leading to improved risk stratification and more effective treatment strategies. Cardiopulmonary exercise testing (CPET) offers valuable aid to investigate functional alterations in subjects with or at risk of HF, while echocardiography can assess cardiac structure and function objectively, both at rest and during exercise (exercise stress echocardiography, ESE). The purpose of this narrative review is to summarise the potential advantages of using an integrated CPET-ESE evaluation in the characterisation of both subjects at risk of developing HF and patients with stable HF