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Introduction: The hemodynamic impact of left atrial (LA) intrinsic properties in heart failure (HF) in relation to heart rate (HR) response to exercise has not received attention. Hypothesis: We aimed at investigating the link between LA stiffness and function vs HR reserve (rest to peak exercise) in patients with HF. Methods: A total of 191 patients with HF: 157 β blockers user (LVEF 38 ± 12%, HR reserve 42 ± 18 beats/min) and 34 Non-β blockers user (LVEF 45 ± 19%, HR reserve 36 ± 19 beats/min) underwent cardiopulmonary exercise testing combined with exercise Echo with assessment of LA strain. LA stiffness (median 0.84, IQR 0.44 to 1.89) was assessed using mitral E/E’ /LA strain ratio at rest. Results: HR reserve was positively associated with LA-strain both at rest (20 ± 11%, R = 0.29) and during exercise (20 ± 11%, R = 0.19), LA-strain rate [absolute value] both at rest (1.7 ± 1.0 /s, R = 0.27) and during exercise (1.6 ± 1.2 /s, R = 0.26) and peak VO 2 (14 ± 4 mL/kg/min, R = 0.62), and negatively associated with LA volume index (44 ± 23 ml/m 2 , R = -0.29), log-transformed LA stiffness (R = -0.35), mitral regurgitation (from 0 to 4+) both at rest (R = -0.28:) and peak exercise (R = -0.25) and VE/VCO 2 slope (32 ± 8, R = -0.32)(figure) (P Conclusions: In HF patients, age and LA stiffness play a key role in HR response to exercise irrespective of β blockers prescription. These data may offer additional insights in the concepts of exercise limitation in HF.

Introduction: The relationship between TAPSE vs heart rate (HR) during physical exercise may well represent the force-frequency relationship of the right ventricular (RV) whose impact on exercise performance and hemodynamics may translate in interesting insight. Aims: to phenotype heart failure (HF) patients based on the response in TAPSE vs HR. Methods: A total of 164 patients with HF and 32 healthy subjects with normal RV to pulmonary circulation (Pc) coupling, left atrium (LA) size and reservoir function (LA volume index 2 and LA-strain >23%) underwent cardiopulmonary exercise testing combined with exercise Echo. TAPSE/HR slope was assessed using (peak TAPSE - rest TAPSE)/(peak HR - rest HR) ratio. According to the 95% confidence interval of TAPSE/HR slope (0.03 - 0.13, median 0.06) in healthy subjects, HF patients were divided into 2 groups: responders (TAPSE/HR ≥0.03, n=108) and non-responders ( Results: There was no significant difference in age (65±12 vs 68±13 years), sex (70 vs 63% male), peak VO 2 (14±4 vs 13±4 ml/kg/min), and VE/VCO 2 slope (32±8 vs 33±10) between responder and non-responder group. However, responders exhibited a higher LA-strain at rest (21±12 vs 17±10%) and exercise (21±12 vs 17±10%), and a lower LA volume index (43±21 vs 52±27 ml/m 2 ) and mitral E/e’ (18±10 vs 22±11) than non-responders, respectively (P Conclusions: The RV force-frequency relationship may be impaired in HF. Especially in non-responders the lack of adaptive RV performance combines with worse RV to Pc coupling and atrial dysfunction. These data may offer additional insights in the concepts of exercise limitation in HF.

Introduction: The heart-kidney interaction in heart failure (HF) is a matter of special interest, especially due to its strong prognostic significance. The search for a reliable, non-invasive parameter with high pathophysiological and prognostic impact to evaluate HF-related renal congestion remains attractive. Doppler evaluation of intra-renal venous flow (IRVF) has been recently employed in HF patients, with a spectrum of findings ranging from a normal continuous flow to a monophasic discontinuous one, indicative of low and high degrees of renal congestion, respectively. Hypothesis: We postulated a role for right atrial dynamics in the renal congestion pathophysiology. The impairment in atrial deformation and pump function may play a primary role increasing the pulsatile backward load in the venous system, especially in acute heart failure (AHF) patients. Methods: 119 consecutive AHF patients were prospectively investigated within 48 hours from admission. Doppler-derived descriptors of renal hemodynamics included the renal arterial resistive index, IRVF pattern, venous impedance index and renal venous stasis index (RVSI). Results: Right atrial peak longitudinal strain (RAPLS) showed a strong correlation with IRVF pattern (Fig A) and various indices of RV function (TAPSE, S’, FAC) and RV coupling as represented by the TAPSE/PASP ratio (Fig B). At multivariate regression analysis, TAPSE/PASP ratio emerged as the main determinant of RVSI. On the other hand, considering only patients with a clearly impaired RV coupling (TAPSE/PASP Conclusions: Our data confirms the main role of the right heart in determining renal stasis in HF patients. When RV to pulmonary circulation uncoupling is severe, the right atrium becomes the key balancing factor in the venous renal flow response. Studies on the mechanistic contribution of the RA dysfunction and the recovery potential of interventions are warranted.

Introduction: The clinical significance of left atrial (LA) involvement and dysfunction in ATTR amyloidosis cardiomyopathy (ATTR-CM) has not been characterized. We sought to study: 1) LA pathology in heart specimens from ATTR-CM patients 2) LA stiffness and mechanics using echocardiographic speckle tracking (EST) in cardiac ATTR-CM 3) the association between parameters of atrial function and mortality. Methods: Congo red staining and immunohistochemistry was performed to assess amyloid in the atria from 5 ATTR-CM heart specimens. 2D EST was used to assess LA reservoir, conduit, contractile function and stiffness in 906 ATTR-CM patients (551 wt ATTR; 93 T60A ATTR; 241 V122I ATTR; and 21 other gene variants). Results: There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, infiltration and remodelling of vessels, capillary disruption and subendocardial fibrosis. EST demonstrated increased atrial stiffness [median (25th-75th quartile) 1.83 (1.15-2.92)] that remained independently associated with reduced survival, after adjusting for known prognostic variables (lnLA stiff: HR= 1.26, CI 1.07-1.57; p=.009). There was substantial impairment of the three phasic functional atrial components [reservoir 8.86(5.94-12.97)%; conduit 6.5(4.53-9.28)%; and contraction 4.0(2.29-6.56)%]. Atrial contractile function was absent in 21.6% of patients whose ECG showed sinus rhythm (SR)-atrial electro-mechanical dissociation (AEMD). AEMD was associated with a poorer prognosis compared to SR patients who had effective mechanical contraction (p Conclusions: The phenotype of ATTR-CM includes clinically significant infiltration of the atrial walls characterized by progressive loss of function and increased stiffness, a strong independent predictor of mortality. AEMD emerged as a distinctive functional phenotype identifying patients in SR with poor prognosis.

Background: In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown. Methods: ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index. Results: At baseline, T1 values showed a negative correlation with left ventricular mass ( r =−0.79; P r =−0.79; P r =−0.54; P r =−0.49; P r =−0.61; P 20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04–6.57; P =0.04), left atrial volume (odds ratio, 1.24; CI, 1.02–1.51; P =0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96–0.99; P =0.03) at baseline were independently associated with clinical worsening at follow-up. Conclusions: In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.

Background— Several cardiovascular diseases are characterized by an impaired O 2 kinetic during exercise. The lack of a linear increase of Δoxygen consumption (V O 2 )/ΔWork Rate (WR) relationship, as assessed by expired gas analysis, is considered an indicator of abnormal cardiovascular efficiency. We aimed at describing the frequency of ΔVO 2 /ΔWR flattening in a symptomatic population of cardiac patients, characterizing its functional profile, and testing the hypothesis that dynamic pulmonary hypertension and right ventricular contractile reserve play a major role as cardiac determinants. Methods and Results— We studied 136 patients, with different cardiovascular diseases, referred for exertional dyspnoea. Cardiopulmonary exercise test combined with simultaneous exercise echocardiography was performed using a symptom-limited protocol. ΔVO 2 /ΔWR flattening was observed in 36 patients (group A, 26.5% of population) and was associated with a globally worse functional profile (reduced peak V O 2 , anaerobic threshold, O 2 pulse, impaired VE/VCO 2 ). At univariate analysis, exercise ejection fraction, exercise mitral regurgitation, rest and exercise tricuspid annular plane systolic excursion, exercise systolic pulmonary artery pressure, and exercise cardiac output were all significantly ( P P =0.01) and exercise tricuspid annular plane systolic excursion (odds ratio, 0.88; confidence interval, 0.80–0.97; P =0.01) as main cardiac determinants of ΔVO 2 /ΔWR flattening; female sex was strongly associated (odds ratio, 6.10; confidence interval, 2.11–17.7; P Conclusions— In patients symptomatic for dyspnea, the occurrence of ΔVO 2 /ΔWR flattening reflects a significantly impaired functional phenotype whose main cardiac determinants are the excessive systolic pulmonary artery pressure increase and the reduced peak right ventricular longitudinal systolic function.

Background: in heart failure (HF) the mitral regurgitation (MR) is clinical and prognostic relevant. Cardiopulmonary exercise testing (CPET) allows evaluating functional capacity and provides indexes for HF risk stratification such as peak oxygen consumption (VO2). Since MR determines a severity-related backward flow to left atrium, it may result in an unfavorable central blood flow exercise redistribution that is physiological relevant to VO2 increase. Aim: To evaluate the cardiac output (CO) and VO2 exercise-response in HF reduced ejection fraction (HFrEF) patients according to MR severity to dissect what mechanism may be predominant in the VO2 increase. Methods: 104 HFrEF patients (mean age 64±11 y, male 72%, ischemic etiology 68%, mean LVEF 34±9%) underwent a maximal CPET (incremental ramp protocol) combined with exercise-echo. CO was non-invasive estimated by echo. Results: Population was divided into 2 groups according to the rest MR: group A (n=80) non-severe MR and B (N=24) severe MR. Despite the groups did not differ in rest CO (A vs B 3.8±1 vs 3.4±1.8 L/min, p=ns) and VO2 (0.27±0.06 vs 0.28±0.09 L/min, p=ns) group B showed higher peripheral extraction (C(a-v)O2 8±2 vs 9±4 mL/100 mL, p=0.036) already at rest (Figure). At peak exercise group B had an impaired increase both in CO (7,0±2,0 vs 5,2±3,3 L/min) and VO2 (1,0±0,3 vs 0,8±0,3 L/min, p=0.001) partially compensated by a greater C(a-v)O2 contribution (15±4 vs 18±5 for A vs B, p=0.047). Conclusions: Severe MR and consequent partial abnormal CO redistribution to the pulmonary circulation seems a relevant pathophysiological mechanisms that limits overall exercise performance in HFrEF. In this high risk subset of patients peripheral extraction compensates for the reduced CO and makes the basis for novel perspectives in these patients.

Background: Right ventricular (RV) dysfunction and pulmonary hypertension (PH) impact on clinical status and have a prognostic value in heart (HF) patients. There is interest in assessment the RV to pulmonary circulation (PC) uncoupling during exercise even though much needs to be defined on the functional phenotypes. Aim: to define how the degrees of RV-PC uncoupling may engender specific functional phenotypes. Methods: 94 HFrEF patients (mean age 66±11 y, male 70%, ischemic etiology 71%, mean LVEF 34±9%) underwent a maximal CPET (incremental ramp protocol) combined with exercise-echo. Results: Population was divided into 4 groups using the 4 quadrant approach (Figure) based on TAPSE vs systolic PAP (PASP) relationship as a length vs developed force of the RV during exercise (cutoff based on median values of 20 mm and 57 mmHg). At peak exercise patients with more favorable TAPSE vs PASP relationship (group A) showed the better functional CPET response (higher peak VO2; lower VE/VCO2 slope and prevalence of exercise oscillatory ventilation (EOV), p= 0.000, 0.005 and 0.000). Group B and C showed similar peak VO2 and the occurrence of dynamic PH (group C) was related to dynamic mitral regurgitation (MR) and high rate of EOV (B vs C p=0.001 and 0.000). Interestingly, for similar exercise tolerance and LV function parameters, group D patients had more severely impaired ventilatory efficiency associated with very high prevalence of rest severe (MR) and EOV (p=0.005, 0.002). Conclusions: This proposed non-invasive RV functional evaluation approach at peak exercise seems appealing for stageing HF syndrome severity based on the degree of the right heart dysfunction. It appears also useful to unmask different ventilatory phenotypes irrespective of a similar impairment in functional capacity and peak VO2.

Background: Speckle tracking analysis is an emerging technique that can be useful to assess abnormalities in cardiac contractility before traditional echo parameters. Purpose: To investigate whether right ventricular (RV) 2D speckle tracking analysis at peak exercise could stratify a heart failure reduced ejection fraction (HFrEF) population in different functional phenotypes, with particular emphasis on RV to pulmonary circulation relationship. Methods: 36 HFrEF patients (mean age 69±12; male 69%; NYHA I-II-III-IV 19-17-25-5 %) underwent a maximal cardiopulmonary exercise testing evaluation (bike, incremental ramp protocol) combined with Echo-Doppler and off-line speckle tracking analysis. Study population was divided in two groups according to median value of 2D right ventricle longitudinal strain at peak exercise (Group A RVLG at peak < -16, 17 patients vs Group B ≥ -16, 19 patients). In all patients we performed traditional echo and 2D longitudinal speckle tracking analysis at rest and peak exercise. Results: Despite similar left ventricle ejection fraction (Group A 36± 9% vs Group B 32±9%, p=ns) and global right ventricle longitudinal strain (RVLG) at rest (Group A -18.6±5.6% vs Group B -14.5±8.2%, p=ns), Group B patients showed a similar exercise performance (Peak VO 2 Group A 31.6±7.4 vs Group B 11.6±3.4 mlO 2 /Kg/min, p=ns) but more impaired ventilation (VE/VCO2 slope Group A 31.6±7.4 vs Group B 37.4±8.8, p Conclusions: In HFrEF RV speckle tracking analysis at peak exercise seems a useful technique for unmasking RV to PC uncoupling and the unfavorable gas exchange and ventilatory phenotypes.

Exercise Ventilatory Power (EVP; peak systolic blood pressure/exercise ventilation to CO2 production slope) is a new powerful prognostic marker that combines ventilator abnormalities with systemic hemodynamic during exercise. The phenotype and clinical relevance of patients with a worse EVP is broadly undefined and we aimed at this definition across a population of heart failure reduced ejection fraction (HFrEF) of different severity. Methods: 77 HFrEF patients (mean age 65±11; male 70%; ischemic etiology 59%; NYHA class I, II, III and IV 23%, 33%, 31% and 13%, respectively; mean LVEF 34±9 %) underwent cardiopulmonary exercise test (CPET) evaluation (ramp protocol on performed on a tilt-table cycleergometer) combined with simultaneous echocardiographic assessment. Results: Patients were divided in 2 EVP classes (cutoff 3) focusing on peak exercise echocardiographic variables. Conclusions: A low EVP translates in a very unfavorable phenotype characterized by a lower peak VO2 and CO response at peak exercise. Remarkable impairment in right heart function and pulmonary hemodynamics were also peculiar of a low EVP. All the LV-pulmonary circulation- RV apparatus is abnormally involved in the exercise response of the EVP HFrEF phenotype.

Background: The ratio between the duration of right ventricular (RV) systole and diastole (S:D ratio) has been proposed as an index of RV performance in a pediatric population with pulmonary arterial hypertension in whom it may predict prognosis and functional capacity. In heart failure (HF) S:D may provide relevant insights in the exercise response. Aim: to analyze the correlation between rest and peak exercise S:D and functional and cardiac parameters in HFrEF. Methods: 94 HFrEF patients (mean age 66±11 y, male 70%, ischemic etiology 71%, mean LVEF 34±9%) underwent a symptom-limited cardiopulmonary exercise testing (incremental ramp protocol) combined with exercise-echo. RV S:D was assessed by echo at rest and peak exercise. Results: A good correlation was found between rest and peak S:D and CPET indexes of exercise capacity, such as peak oxygen consumption (VO2) (Sperman’s rho -0.40 and 0.38 respectively, p= 0.02 and 0.023) and maximal workload (Rho= -0.42 and -0.45, p=0.031 and 0.034). An higher S:D also correlated with more impaired ventilatory efficiency or higher VE/VCO2 slope (Rho 0.49 and 0.32, p=0.019 and 0.024). Looking at echo phenotype, interestingly S:D is associated with parameters of mitral regurgitation (MR) severity, such as effective regurgitant orifice (Rho rest 0.63, peak 0.35, p

Background: In heart failure (HF) patients the severity of mitral regurgitation (MR) at rest has a well established prognostic value and its increase during exercise further adds to an increased risk. Our goal was to define the relationship between the degree of exercise MR severity with cardiopulmonary and echocardiographic related phenotypes in a cohort of HF patients. Methods: 71 HF reduced ejection fraction patients (mean age 67±11; male 72%; ischemic etiology 61%; NYHA class I, II, III and IV 13%, 36%, 39% and 12%, mean ejection fraction 33±9%) underwent cardiopulmonary exercise test (CPET) on tiltable cycle-ergometer combined with echocardiography at rest and during exercise. The population was divided into two groups according to the degree of functional peak MR: no to mild/moderate MR (no MR, MR1+ and MR2+) vs moderate/severe MR (MR3+ and MR4+). Results: A good correlation (ρ coefficient= 0.49) was found between the degree of dynamic MR and PASP at peak exercise. Despite similar echocardiographic profile at rest patients with significant peak MR (MR≥3+) had worse exercise performance (lower peak VO2, O2 pulse and workload) and impaired ventilatory efficiency (higher VE/VCO2 slope). Conclusions: In HF patients the severity of exercise-induced MR is associated with the most unfavorable performance and pulmonary hemodynamic response. A combined approach with CPET and echocardiographic assessment can help to early unmask and target functional MR and its related unfavorable phenotypes.

To the Editor: We read with interest the article by Kato et al1 recently published in Circulation: Heart Failure . Findings add to the series of reports suggesting that combining cardiopulmonary exercise test and natriuretic peptide levels in a population of potential heart transplant candidates strengthens risk stratification accuracy. Especially for comparable levels of peak VO2, patients with lower brain natriuretic peptide (BNP) exhibited a prognosis similar to heart transplant recipients. To further …