Age Differences in Cardiopulmonary Exercise Testing Parameters in Heart Failure with Reduced Ejection Fraction.

Background and Objectives: Cardiopulmonary exercise testing (CPET) is a cornerstone of risk stratification in heart failure with reduced ejection fraction (HFrEF). However, there is a paucity of evidence on its predictive power in older patients. The aim of this study was to evaluate the prognostic power of current heart transplantation (HTx) listing criteria in HFrEF stratified according to age groups. Materials and Methods: Consecutive patients with HFrEF undergoing CPET between 2009 and 2018 were followed-up for cardiac death and urgent HTx. Results: CPET was performed in 458 patients with HFrEF. The composite endpoint occurred in 16.8% of patients ≤50 years vs. 14.1% of patients ≥50 years in a 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percentage of predicted pVO2 were strong independent predictors of outcomes. The International Society for Heart and Lung Transplantation thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers), VE/VCO2 slope > 35 and percentage of predicted pVO2 ≤ 50% presented a higher overall diagnostic effectiveness in younger patients (≤50 years). Specific thresholds for each age subgroup outperformed the traditional cut-offs. Conclusions: Personalized age-specific thresholds may contribute to an accurate risk stratification in HFrEF. Further studies are needed to address the gap in evidence between younger and older patients.

Relationship of left ventricular global longitudinal strain with cardiac autonomic denervation as assessed by 123I-mIBG scintigraphy in patients with heart failure with reduced ejection fraction submitted to cardiac resynchronization therapy : Assessment of cardiac autonomic denervation by GLS in patients with heart failure with reduced ejection fraction submitted to CRT.

BACKGROUND: Heart failure (HF) is associated with cardiac autonomic denervation (AD), which can be non-invasively assessed by 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy and has prognostic implications. We aimed to study the relationship between myocardial contractility assessed by global longitudinal strain (GLS) and AD assessed by 123I-mIBG scintigraphy in advanced HF. METHODS/RESULTS: BETTER-HF is a prospective randomized clinical trial including HF patients (pts) submitted to cardiac resynchronization therapy (CRT) who are submitted to a clinical, echocardiographic, and scintigraphic assessment before and 6 months after CRT. 81 pts were included. An echocardiographic response (absolute increase in left ventricular ejection fraction ≥ 10%) was observed in 73.7% of pts. A higher baseline late heart-to-mediastinum ratio (HMR) was associated with a better echocardiographic response. There was a significant association between late HMR and GLS at baseline and 6 months. At baseline, GLS had an AUC of 0.715 for discrimination for a late HMR < 1.6. A GLS cut-off of - 9% maximized the likelihood of correctly classifying a pt as having severe AD (HMR < 1.6). CONCLUSION: Myocardial contractility as assessed by GLS is moderately correlated with AD as assessed by 123I-mIBG scintigraphy and has a good discrimination for the identification of severe cardiac denervation. GLS may allow for a more readily accessible estimation of the degree of AD in advanced HF pts.

Cardiotoxicity in breast cancer treatment: What about left ventricular diastolic function and left atrial function?

AIMS: Cardiotoxicity is a possible complication of cancer treatment, particularly with anthracyclines and anti-HER2 drugs. Systolic dysfunction has already been described. Diastolic dysfunction and left atrial function are less studied. We sought to analyze the impact of cardiotoxic treatments on left ventricular diastolic function and left atrial (LA) function. METHODS AND RESULTS: Retrospective study of 100 patients (all women, with a mean age of 54 ± 12 years) with three exams in the span of 1 year during treatment for breast cancer. Patients with previous cancer treatment, coronary artery disease, significant valvular disease, and atrial arrhythmias were excluded. Diastolic dysfunction was classified according to international guidelines and left atrial strain was analyzed by two-dimensional speckle tracking. In our sample, 74% received anthracyclines, 83% anti-HER2, and 76% radiation treatment. In the follow-up, 20% developed new or worsening diastolic dysfunction. Age was the only independent predictor (OR 1.93, 95% CI 1.04-3.58, P = .037). In left atrial function, only the contractile function was significantly reduced in 20.8% of the patients and age was also the only independent predictor, but with a protective effect (OR 0.51, 95% CI 0.28-0.91, P = .023). CONCLUSIONS: During breast cancer treatment, 20% of the patients develop new or worsening diastolic dysfunction, being age the main determinant, suggesting higher impact of chemotherapy in older patients. Contractile left atrial function is also compromised but, in this case, age seems to be protective. Our results support a stricter surveillance in older patients together to eventually adjust chemotherapy regimens.

Prognostic power of anaerobic threshold parameters in patients with transposition of the great arteries and systemic right ventricle.

INTRODUCTION: Both transposition of the great arteries (TGA) previously submitted to a Senning/Mustard procedure and congenitally corrected TGA (cc-TGA) have the systemic circulation supported by the morphological right ventricle, thereby rendering these patients to heart failure events risk. The aim of this study was to evaluate cardiopulmonary exercise test parameters for stratifying the risk of heart failure events in TGA patients. METHODS: Retrospective evaluation of adult TGA patients with systemic circulation supported by the morphological right ventricle submitted to cardiopulmonary exercise test in a tertiary centre. Patients were followed up for at least 1 year for the primary endpoint of cardiac death or heart failure hospitalisation. Several cardiopulmonary exercise test parameters were analysed as potential predictors of the combined endpoint and their predictive power were compared (area under the curve). RESULTS: Cardiopulmonary exercise test was performed in 44 TGA patients (8 cc-TGA), with a mean age of 35.1 ± 8.4 years. The primary endpoint was reached by 10 (22.7%) patients, with a mean follow-up of 36.7 ± 26.8 months. Heart rate at anaerobic threshold had the highest area under the curve value (0.864), followed by peak oxygen consumption (pVO2) (0.838). Heart rate at anaerobic threshold ≤95 bpm and pVO2 ≤20 ml/kg/min had a sensitivity of 87.5 and 80.0% and a specificity of 82.4 and 76.5%, respectively, for the primary outcome. CONCLUSION: Heart rate at anaerobic threshold ≤95 bpm had the highest predictive power of all cardiopulmonary exercise test parameters analysed for heart failure events in TGA patients with systemic circulation supported by the morphological right ventricle.

Modified continuity equation using left ventricular outflow tract three-dimensional imaging for aortic valve area estimation.

PURPOSE: Aortic valve area (AVA) is usually estimated by the continuity equation (CE) in which the left ventricular outflow tract (LVOT) area is calculated assuming a circular shape. This study aimed to compare measurements of LVOT area using standard 2D transthoracic echocardiography (2DTTE), 3D transesophageal echocardiography (3DTEE), and multidetector computed tomography (MDCT) and assess their relative impact on AVA estimated by the CE. METHODS AND RESULTS: We prospectively enrolled 60 patients with severe aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR) who systematically underwent 2DTTE, 3DTEE, and MDCT. Mean LVOT areas obtained by 2DTTE (3.28±0.66 cm2 ) and 3DTEE (3.95±0.90 cm2 ) were significantly underestimated when compared to the mean MDCT LVOT area (4.31±0.99 cm2 ). LVOT was rather elliptical than round, with a mean eccentricity index of 1.47 (ratio of maximum to minimum LVOT diameters) assessed by MDCT. Mean TTE AVA estimated by the CE was 0.62±0.20 cm2 . Substitution of 2DTTE LVOT area by 3DTEE LVOT area in the CE resulted in AVA of 0.74±0.24 cm2 , while using MDCT LVOT area held an AVA of 0.80±0.24 cm2 . MDCT-derived AVA was similar to MDCT planimetric AVA and allowed 24% of patients to be reclassified from severe to moderate AS. CONCLUSIONS: 2DTTE and 3DTEE underestimate LVOT area when compared to MDCT with significant impact on AVA estimation. Assessment through MDCT fusion AVA may be of incremental value in patients with discrepant severity criteria for AS.

GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome.

NMDA receptors play a central role in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the CNS. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial. We report a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic levels of AMPA receptors are increased and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor. We used quantitative proteomic analysis to identify changes in the composition of postsynaptic densities from GluN2B(-/-) mouse primary neuronal cultures and found altered levels of several ubiquitin proteasome system components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator restored the synaptic levels of AMPA receptors in GluN2B(-/-) neurons and their endocytosis, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions.

Global left ventricular myocardial work index and medium-term adverse cardiovascular events after ST-elevation myocardial infarction.

BACKGROUND: Left ventricular global longitudinal strain (GLS) has incremental prognostic value over ejection fraction (EF) in patients with ST-segment-elevation myocardial infarction (STEMI), but it is also load dependent. It has been recently demonstrated that Myocardial work (MW), integrating blood pressure with GLS, predicts long-term all-cause mortality. We aimed to further explore the prognostic value of MW for cardiovascular endpoints in patients with STEMI. METHODS AND RESULTS: Retrospective study of 200 consecutive patients admitted with a STEMI, mean age of 62 (SD 12) years, 79.5% males, that survived to discharge. Transthoracic echocardiography was performed before discharge (5 ± 3 days after admission). Mean follow-up was 790 days. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, and unplanned cardiovascular admission (ACE). During follow-up, 26 patients had a ACE. In univariable Cox regression analysis, male gender, body mass index, GRACE risk score and Global Work Index (GWI) were selected to the multivariable analysis, in which, only GWI (per 100 mmHg% decrease: hazard ratio estimate 1.19, 95% confidence interval 1.07-1.34, p-value = 0.002) remained independently associated with ACE, with effective reclassification of non-events. The best GWI cut-off to predict ACE was ≤1165 mmHg% (Log-rank, p = 0.034). CONCLUSIONS: LV GWI is independently associated with medium-term ACE. Nevertheless, prospective studies in a larger sample of patients are warranted to confirm this finding.

Evaluation of left atrial strain imaging and integrated backscatter as predictors of recurrence in patients with paroxysmal, persistent, and long-standing persistent atrial fibrillation undergoing catheter ablation.

BACKGROUND: Impaired left atrial (LA) strain predicts atrial fibrillation (AF) recurrence after catheter ablation (CA), but currently there is no cut-off to guide patient selection for CA. Integrated backscatter (IBS) is a promising tool for noninvasive quantification of myocardial fibrosis. The aim of this study was to compare LA strain and IBS between paroxysmal, persistent, and long-standing persistent AF and evaluate their association with AF recurrence after CA. METHODS: Analysis of consecutive patients with symptomatic paroxysmal and persistent AF who underwent CA. LA phasic strain, strain rate and IBS were assessed by two-dimensional speckle-tracking at baseline. RESULTS: We analyzed 78 patients, 31% with persistent AF (46% long-standing AF), 65% male, mean age 59 ± 14 years, who underwent CA and were followed-up for 12 months. AF recurrence occurred in 22 (28%) patients. LA phasic strain parameters were significantly impaired in patients with AF recurrence and were independent predictors of AF recurrence in a multivariable analysis. LA reservoir strain (LASr) < 18% predicted AF recurrence with 86% sensitivity and 71% specificity, with a higher predictive power compared to LA volume index (LAVI). LASr < 22% in paroxysmal AF and LASr < 12% in persistent AF correlated with AF recurrence. Increased IBS was a predictor of AF recurrence in patients with paroxysmal AF. CONCLUSION: LA phasic strain parameters were predictors of AF recurrence after CA, independently of LAVI and AF subtype. LASr < 18% showed a higher predictive power compared to LAVI. Further studies are needed to investigate the role of IBS as a predictor of AF recurrence.

Contactin-associated protein 1 (Caspr1) regulates the traffic and synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors.

Glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type mediate fast excitatory synaptic transmission in the CNS. Synaptic strength is modulated by AMPA receptor binding partners, which regulate receptor synaptic targeting and functional properties. We identify Contactin-associated protein 1 (Caspr1) as an AMPA receptor interactor. Caspr1 is present in synapses and interacts with AMPA receptors in brain synaptic fractions. Coexpression of Caspr1 with GluA1 increases the amplitude of glutamate-evoked currents. Caspr1 overexpression in hippocampal neurons increases the number and size of synaptic GluA1 clusters, whereas knockdown of Caspr1 decreases the intensity of synaptic GluA1 clusters. Hence, Caspr1 is a regulator of the trafficking of AMPA receptors to synapses.

Cardiopulmonary Exercise Testing in the Age of New Heart Failure Therapies: Still a Powerful Tool?

BACKGROUND: New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). METHODS: Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. RESULTS: CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. CONCLUSION: ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

Sacubitril/Valsartan Improves Left Atrial and Ventricular Strain and Strain Rate in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Data on the impact of sacubitril/valsartan (SV) therapy on phasic left atrial (LA) and left ventricular (LV) strain in heart failure with reduced ejection fraction (HFrEF) are limited. The aim of this study was to evaluate changes in two-dimensional speckle tracking (2D-STE) parameters with SV therapy in HFrEF patients. METHODS: Prospective evaluation of HFrEF patients receiving optimized medical therapy. Two-dimensional speckle tracking (2D-STE) parameters were assessed at baseline and after 6 months of SV therapy. LA strain and strain rate (SR) in reservoir, conduit, and contraction phases were compared with LV longitudinal, radial, and circumferential strain and SR and stratified according to heart rhythm and HFrEF etiology. RESULTS: A total of 35 patients completed the 6-month follow-up, with a mean age of 59 ± 11 years, 40% in atrial fibrillation, 43% with ischemic etiology, and LVEF of 29 ± 6%. There were significant improvements in LA reservoir, conduit, and contractile strain and SR following SV therapy, particularly among patients in sinus rhythm. There were significant improvements in longitudinal, radial, and circumferential LV function indices. CONCLUSION: SV therapy in HFrEF was associated with improved longitudinal, radial, and circumferential function, particularly among patients in sinus rhythm. These findings can provide insights into the mechanisms underlying the improvement of cardiac function and help assess subclinical responses to the treatment.

Cardiopulmonary Exercise Testing in Patients with Heart Failure: Impact of Gender in Predictive Value for Heart Transplantation Listing.

BACKGROUND: Exercise testing is key in the risk stratification of patients with heart failure (HF). There are scarce data on its prognostic power in women. Our aim was to assess the predictive value of the heart transplantation (HTx) thresholds in HF in women and in men. METHODS: Prospective evaluation of HF patients who underwent cardiopulmonary exercise testing (CPET) from 2009 to 2018 for the composite endpoint of cardiovascular mortality and urgent HTx. RESULTS: A total of 458 patients underwent CPET, with a composite endpoint frequency of 10.5% in females vs. 16.0% in males in 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percent of predicted pVO2 were independent discriminators of the composite endpoint, particularly in women. The International Society for Heart Lung Transplantation recommended values of pVO2 ≤ 12 mL/kg/min or ≤14 if the patient is intolerant to ß-blockers, VE/VCO2 slope > 35, and percent of predicted pVO2 ≤ 50% showed a higher diagnostic effectiveness in women. Specific pVO2, VE/VCO2 slope and percent of predicted pVO2 cut-offs in each sex group presented a higher prognostic power than the recommended thresholds. CONCLUSION: Individualized sex-specific thresholds may improve patient selection for HTx. More evidence is needed to address sex differences in HF risk stratification.

Impact of repaired aortic coarctation in left ventricular myocardial work.

AIMS: Myocardial strain analysis enables more precise assessment of cardiac performance but is relatively load dependent. New tools have been developed with afterload adjustment. Our objective was to assess myocardial work (MW) in patients with repaired aortic coarctation (rACo). METHODS: Prospective study of consecutive patients with rACo who underwent a routine transthoracic echocardiogram in 2018 and 2019 at our center. Patients with significant aortic valve disease, pacemaker, or other congenital heart diseases (except for mild bicuspid aortic valve disease) were excluded. Global longitudinal strain with two dimensional speckle tracking analysis and MW were obtained (GWI:Global Work Index; GCW: Global Constructive Work; GWW: Global Wasted Work; GWE: Global Work Efficiency). Blood pressure was measured in the patient's right arm. RESULTS: We included 42 patients in the analysis, mean age of 37±10 years, 38% males. In this group, 52% had hypertension and 64% had a concomitant bicuspid aortic valve. In comparison to previously published reference values, patients with rACo had significantly lower GWI (1807 vs. 1896 mmHg%) and GCW (2173 vs. 2232 mmHg%) (p<0.001), particularly in males. Systolic blood pressure is an independent predictor for GWI (ß=0.432) and for GCW (ß=0.534) and GLS an independent predictor of all MW parameters (ß>0.594). Neither age nor gender were independent predictors. CONCLUSIONS: In patients with rACo, there are some signs of left ventricular dysfunction with a reduction in GCW and GWI and with preserved GWE, despite normal ejection fraction and strain.

Predictive Ability of Cardiopulmonary Exercise Test Parameters in Heart Failure Patients with Cardiac Resynchronization Therapy. / Capacidade Preditiva dos Parâmetros do Teste de Esforço Cardiopulmonar em Pacientes com Insuficiência Cardíaca em Terapia de Ressincronização Cardíaca.

BACKGROUND: There is evidence suggesting that a peak oxygen uptake (pVO2) cut-off of 10ml/kg/min provides a more precise risk stratification in cardiac resynchronization therapy (CRT) patients. OBJECTIVE: To compare the prognostic power of several cardiopulmonary exercise testing (CPET) parameters in this population and assess the discriminative ability of the guideline-recommended pVO2cut-off values. METHODS: Prospective evaluation of consecutive heart failure (HF) patients with left ventricular ejection fraction ≤40%. The primary endpoint was a composite of cardiac death and urgent heart transplantation (HT) in the first 24 follow-up months, and was analysed by several CPET parameters for the highest area under the curve (AUC) in the CRT group. A survival analysis was performed to evaluate the risk stratification provided by several different cut-offs. p values <0.05 were considered significant. RESULTS: A total of 450 HF patients, of which 114 had a CRT device. These patients had a higher baseline risk profile, but there was no difference regarding the primary outcome (13.2% vs 11.6%, p =0.660). End-tidal carbon dioxide pressure at anaerobic threshold (PETCO2AT)had the highest AUC value, which was significantly higher than that of pVO2in the CRT group (0.951 vs 0.778, p =0.046). The currently recommended pVO2cut-off provided accurate risk stratification in this setting (p <0.001), and the suggested cut-off value of 10 ml/min/kg did not improve risk discrimination in device patients (p =0.772). CONCLUSION: PETCO2ATmay outperform pVO2's prognostic power for adverse events in CRT patients. The current guideline-recommended pVO2 cut-off can precisely risk-stratify this population.

FUNDAMENTO: Há evidências sugerindo que um corte do pico de consumo de oxigênio (pVO2) de 10ml/kg/min fornece uma estratificação de risco mais precisa em pacientes com Terapia de Ressincronização Cardíaca (TRC). OBJETIVO: Comparar o poder prognóstico de vários parâmetros do teste cardiopulmonar de exercício (TCPE) nesta população e avaliar a capacidade discriminativa dos valores de corte de pVO2 recomendados pelas diretrizes. MÉTODOS: Avaliação prospectiva de uma série consecutiva de pacientes com insuficiência cardíaca (IC) com fração de ejeção do ventrículo esquerdo ≤40%. O desfecho primário foi um composto de morte cardíaca e transplante cardíaco urgente (TC) nos primeiros 24 meses de acompanhamento, e foi analisado por vários parâmetros do TCPE para a maior área sob a curva (AUC) no grupo TRC. Uma análise de sobrevida foi realizada para avaliar a estratificação de risco fornecida por vários pontos de corte diferentes. Valores de p < 0,05 foram considerados significativos. RESULTADOS: Um total de 450 pacientes com IC, dos quais 114 possuíam aparelho de TRC. Esses pacientes apresentaram um perfil de risco basal mais alto, mas não houve diferença em relação ao desfecho primário (13,2% vs 11,6%, p = 0,660). A pressão expiratória de dióxido de carbono no limiar anaeróbico (PETCO2AT) teve o maior valor de AUC, que foi significativamente maior do que o de pVO2 no grupo TRC (0,951 vs 0,778, p = 0,046). O valor de corte de pVO2 atualmente recomendado forneceu uma estratificação de risco precisa nesse cenário (p <0,001), e o valor de corte sugerido de 10 ml/min/kg não melhorou a discriminação de risco em pacientes com dispositivos (p = 0,772). CONCLUSÃO: A PETCO2AT pode superar o poder prognóstico do pVO2 para eventos adversos em pacientes com TRC. O ponto de corte de pVO2 recomendado pelas diretrizes atuais pode estratificar precisamente o risco dessa população.

Blunted coronary flow velocity reserve is associated with impairment in systolic function and functional capacity in hypertrophic cardiomyopathy.

BACKGROUND: Coronary microvascular dysfunction constitutes an important pathophysiological feature in hypertrophic cardiomyopathy (HCM). We aimed to assess the association between impaired coronary flow velocity reserve (CFVR) and ventricular systolic function and functional capacity. METHODS: Eighty-three patients with HCM were enrolled in this prospective cohort study. Patients underwent echocardiogram to evaluate ventricular performance and CFVR in the left anterior descending artery (LAD) and posterior descending artery (PD). Diastolic coronary flow velocity was measured in basal conditions and in hyperemia. CFVR was calculated as the ratio of hyperemic and basal peak diastolic flow velocities. Functional capacity was evaluated by cardiopulmonary exercise testing (CPET). The link between CFVR and biventricular systolic function and peak VO2 was studied. RESULTS: Age was 55.0(14.4)years, 50 patients (60%) were male; 59 patients (71%) had nonobstructive HCM. Mean CFVR LAD was 1.81(0.49) and CFVR PD was 1.73(0.55). Lower CFVR PD was associated with impaired global longitudinal strain (GLS) 2D (ß-estimate:-3.240,95%CI:-4.634;-1.846, p < 0.001), GLS 3D (ß-estimate:-2.559,95%CI:-3.932;-1.186, p < 0.001) and area strain (ß-estimate:-3.044,95%CI:-5.373;-0.716, p = 0.011). Lower values of CFVR PD related to worse global work index (ß-estimate:267.824,95%CI:75.964;459.683, p = 0.007), global constructive work (ß-estimate:217.300,95%CI:38.750;395.850, p = 0.018) and global work efficiency (ß-estimate:5.656,95%CI:2.229;9.084, p = 0.002). Impaired CFVR LAD (ß-estimate:2.826, 95%CI:0.913;4.739, p = 0.004) and CFVR PD (ß-estimate:2.801,95%CI:0.657;4.945, p = 0.011) were associated with lower TAPSE. Lower values of CFVR LAD (ß-estimate:2.580, 95%CI:0.169;4.991, p = 0.036) and CFVR PD (ß-estimate:3.163, 95%CI: 0.721;5.606, p = 0.012) were associated with worse peak VO2. CONCLUSION: Lower CFVR was associated with impairment in biventricular systolic function parameters and functional capacity assessed by pVO2.

The Impact of Ischemia Assessed by Magnetic Resonance on Functional, Arrhythmic, and Imaging Features of Hypertrophic Cardiomyopathy.

Aims: The aim of the study is to investigate the association between the degree of ischemia due to coronary microvascular dysfunction (CMD) and the left ventricular (LV) tissue characteristics, systolic performance, and clinical manifestations in hypertrophic cardiomyopathy (HCM). Methods and Results: This prospective study enrolled 75 patients with HCM without obstructive epicardial coronary artery disease. Each patient underwent cardiovascular magnetic resonance (CMR) including parametric mapping, perfusion imaging during regadenoson-induced hyperemia, late gadolinium enhancement (LGE) and three-dimensional longitudinal, circumferential, and radial strains analysis. Electrocardiogram, 24-h Holter recording, and cardiopulmonary exercise testing (CPET) were performed to assess arrhythmias and functional capacity. In total, 47 (63%) patients were men with the mean age of 54.6 (14.8) years, 51 (68%) patients had non-obstructive HCM, maximum wall thickness (MWT) was 20.2 (4.6) mm, LV ejection fraction (LVEF) was 71.6 (8.3%), and ischemic burden was 22.5 (16.9%) of LV. Greater MWT was associated with the severity of ischemia (ß-estimate:1.353, 95% CI:0.182; 2.523, p = 0.024). Ischemic burden was strongly associated with higher values of native T1 (ß-estimate:9.018, 95% CI:4.721; 13.315, p < 0.001). The association between ischemia and LGE was significant in following subgroup analyses: MWT 15-20 mm (ß-estimate:1.941, 95% CI:0.738; 3.143, p = 0.002), non-obstructive HCM (ß-estimate:1.471, 95% CI:0.258; 2.683, p = 0.019), women (ß-estimate:1.957, 95% CI:0.423; 3.492, p = 0.015) and age <40 years (ß-estimate:4.874, 95% CI:1.155; 8.594, p = 0.016). Ischemia in ≥21% of LV was associated with LGE >15% (AUC 0.766, sensitivity 0.724, specificity 0.659). Ischemia was also associated with atrial fibrillation or flutter (AF/AFL) (OR-estimate:1.481, 95% CI:1.020; 2.152, p = 0.039), but no association was seen for non-sustained ventricular tachycardia. Ischemia was associated with shorter time to anaerobic threshold (ß-estimate: -0.442, 95% CI: -0.860; -0.023, p = 0.039). Conclusion: In HCM, ischemia associates with morphological markers of severity of disease, fibrosis, arrhythmia, and functional capacity.

Prognostic value of VE/VCO2 slope in overweight heart failure patients.

BACKGROUND: A decreased hypercapnic ventilatory response of the overweight patients would lower the ventilation equivalent of carbon dioxide (VE/VCO2) slope but worsen prognosis. The aim of this study was to compare the prognostic ability of the VE/VCO2 slope and peak oxygen consumption (pVO2) between normal and overweight heart failure (HF) patients. METHODS: Prospective evaluation of ambulatory patients with reduced left ventricular ejection fraction who underwent baseline assessment with a cardiopulmonary exercise test. The primary endpoint was cardiac death or urgent heart transplantation in the 5-year period of follow-up. The predictive power of VE/VCO2 slope and pVO2 were compared (area under the curve (AUC) analysis and Hanley & McNeil test), in the subgroups of patients with body mass index (BMI) of 18.5-24.9 kg/m2 and ≥ 25 kg/m2. Statistical differences with a p value < 0.05 were considered significant. RESULTS: There were 270 enrolled patients, with a mean BMI of 27 ± 4 kg/m2. No differences between normal and overweight patients (38.0% vs 29.8%, P=0.170) were found during the 5-year period for the primary endpoint. The VE/VCO2 slope was non-inferior to pVO2 in both groups at 1, 3 and 5 years of follow-up. The comparison of VE/VCO2 slope between groups revealed a significant lower AUC at 3 (0.921 vs 0.787, P=0.022) and 5 years (0.898 vs 0.787, P=0.044) of follow-up for overweight patients. CONCLUSION: Despite VE/VCO2 slope provides a discriminative power at least as good as pVO2 for predicting adverse events in both normal and overweight HF patients, a significant lower predictive power was found in overweight patients.

Impact of Cardiorespiratory Fitness on the Obesity Paradox in Heart Failure with Reduced Ejection Fraction. / O Impacto da Aptidão Cardiorrespiratória no Paradoxo da Obesidade em Insuficiência Cardíaca com Fração de Ejeção Reduzida.

BACKGROUND: Higher body mass index (BMI) has been associated with improved outcomes in heart failure with reduced ejection fraction. This finding has led to the concept of the obesity paradox. OBJECTIVE: To investigate the impact of exercise tolerance and cardiorespiratory capacity on the obesity paradox. METHODS: Outpatients with symptomatic heart failure and left ventricular ejection fraction (LVEF) ≤ 40%, followed up in our center, prospectively underwent baseline comprehensive evaluation including clinical, laboratorial, electrocardiographic, echocardiographic, and cardiopulmonary exercise testing parameters. The study population was divided according to BMI (< 25, 25 - 29.9, and ≥ 30 kg/m2). All patients were followed for 60 months. The combined endpoint was defined as cardiac death, urgent heart transplantation, or need for mechanical circulatory support. P value < 0.05 was considered significant. RESULTS: In the 282 enrolled patients (75% male, 54 ± 12 years, BMI 27 ± 4 kg/m2, LVEF 27% ± 7%), the composite endpoint occurred in 24.4% during follow-up. Patients with higher BMI were older, and they had higher LVEF and serum sodium levels, as well as lower ventilatory efficiency (VE/VCO2) slope. VE/VCO2 and peak oxygen consumption (pVO2) were strong predictors of prognosis (p < 0.001). In univariable Cox regression analysis, higher BMI was associated with better outcomes (HR 0.940, CI 0.886 - 0.998, p 0.042). However, after adjusting for either VE/VCO2 slope or pVO2, the protective role of BMI disappeared. Survival benefit of BMI was not evident when patients were grouped according to cardiorespiratory fitness class (VE/VCO2, cut-off value 35, and pVO2, cut-off value 14 mL/kg/min). CONCLUSION: These results suggest that cardiorespiratory fitness outweighs the relationship between BMI and survival in patients with heart failure.

FUNDAMENTO: Índice de massa corporal (IMC) elevado tem sido associado a desfechos melhores em pacientes com insuficiência cardíaca com fração de ejeção reduzida. Este achado tem levado ao conceito do paradoxo da obesidade. OBJETIVO: Investigar o impacto de tolerância ao exercício e capacidade cardiorrespiratória no paradoxo da obesidade. MÉTODO: Pacientes ambulatoriais com insuficiência cardíaca sintomática e fração de ejeção ventricular esquerda (FEVE) ≤ 40%, acompanhados no nosso centro, foram prospectivamente submetidos à avaliação abrangente de linha de base incluindo parâmetros clínicos, laboratoriais, eletrocardiográficos, ecocardiográficos e de exercício cardiopulmonar. A população do estudo foi dividida de acordo com o IMC (< 25, 25 ­ 29,9 e ≥ 30 kg/m2). Todos os pacientes foram acompanhados durante 60 meses. O desfecho composto foi definido como morte cardíaca, transplante cardíaco urgente ou necessidade de suporte circulatório mecânico. Valores de p < 0,05 foram considerados significativos. RESULTADOS: Dos 282 pacientes incluídos (75% masculino, 54 ± 12 anos, IMC 27 ± 4 kg/m2, FEVE 27% ± 7%), o desfecho composto ocorreu em 24,4% durante o acompanhamento. Os pacientes com IMC elevado eram mais velhos e apresentavam FEVE e níveis séricos de sódio mais elevados, bem como menor inclinação de eficiência ventilatória (VE/VCO2). VE/VCO2 e consumo de oxigênio de pico (VO2p) eram fortes preditores prognósticos (p < 0,001). Na análise univariada de regressão de Cox, o IMC elevado foi associado a desfechos melhores (razão de risco 0,940, intervalo de confiança 0,886 ­ 0,998, p 0,042). Porém, após ajustar para ou inclinação VE/VCO2 ou VO2p, o papel protetor do IMC sumiu. O benefício de sobrevida do IMC não foi evidente quando os pacientes foram agrupados de acordo com a classe de aptidão cardiorrespiratória (VE/VCO2, valor de corte de 35, e VO2p, valor de corte de 14 mL/kg/min). CONCLUSÃO: Estes resultados sugerem que a aptidão cardiorrespiratória supera a relação entre o IMC e a sobrevida em pacientes com insuficiência cardíaca.

Prognostic Prediction of Cardiopulmonary Exercise Test Parameters in Heart Failure Patients with Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with increased mortality in heart failure (HF) patients. OBJECTIVE: To evaluate whether the risk of AF patients can be precisely stratified by relation with cardiopulmonary exercise test (CPET) cut-offs for heart transplantation (HT) selection. METHODS: Prospective evaluation of 274 consecutive HF patients with left ventricular ejection fraction ≤ 40%. The primary endpoint was a composite of cardiac death or urgent HT in 1-year follow-up. The primary endpoint was analysed by several CPET parameters for the highest area under the curve and for positive (PPV) and negative predictive value (NPV) in AF and sinus rhythm (SR) patients to detect if the current cut-offs for HT selection can precisely stratify the AF group. Statistical differences with a p-value <0.05 were considered significant. RESULTS: There were 51 patients in the AF group and 223 in the SR group. The primary outcome was higher in the AF group (17.6% vs 8.1%, p = 0.038). The cut-off value of pVO2 for HT selection showed a PPV of 100% and an NPV of 95.5% for the primary outcome in the AF group, with a PPV of 38.5% and an NPV of 94.3% in the SR group. The cut-off value of VE/VCO2 slope showed lower values of PPV (33.3%) and similar NPV (92.3%) to pVO2 results in the AF group. CONCLUSION: Despite the fact that AF carries a worse prognosis for HF patients, the current cut-off of pVO2 for HT selection can precisely stratify this high-risk group.

C-reactive protein reduction with sacubitril-valsartan treatment in heart failure patients.

OBJECTIVE: C-Reactive Protein (CRP) has emerged as an accessible measured product of inflammation. Whether systemic inflammation, a common feature of Heart Failure (HF), can be reduced by HF treatments in not well established. Sacubitril/Valsartan had prognosis benefit demonstrated in the PARADIGM-HF trial and was able to reduce proinflammatory cytokines in preclinical animal studies. However, no human studies evaluated if the benefits of this therapy are mediated by anti-inflammatory effects too. The aim of this study was to prospectively compare CRP values before and six months after Sacubitril-Valsartan therapy. METHODS: Prospective evaluation of chronic HF patients with left ventricular ejection fraction ≤ 40% despite optimized standard of care therapy, in which Sacubitril/Valsartan therapy was started and no additional HF treatment was expected to change. Clinical, laboratorial (including CRP values), electrocardiographic, transthoracic echocardiography and cardiopulmonary exercise test (CPET) data were gathered in the week before starting Sacubitril/Valsartan therapy and six months thereafter. RESULTS: There were 42 patients with a mean age of 59 ± 11 years, of which 35 completed the six months of follow-up, since 2 patients died and 5 discontinued treatment for adverse events. Patients with baseline CRP values above the median (> 2.5 mg/L) had a significantly higher percentage of New York Heart Association class ≥ III (65% vs. 33%, P=0.028) and a reduced exercise time in CPET (361 ± 297 vs. 575 ± 265 seconds, P=0.034). After 6 months of Sacubitril-Valsartan therapy, 24 (69%) patients had an improvement in CRP values with a significantly reduction as compared to baseline (median 2.5 mg/L (Interquartile range (IQR) 1.3-5.0) vs. 2.2 mg/L (IQR 0.9-4.0), P=0.014 in the Wilcoxon test). In the group of 17 (49%) patients with at least 25% improvement in CRP values with Sacubitril/Valsartan therapy, the benefit of several clinical, CPET and echocardiographic parameters were not significantly different from the benefit of patients with no improvement or an improvement inferior to 25% in CRP values. CONCLUSION: Sacubitril/Valsartan therapy was able to reduce CRP values in a chronic HF population. Whether this reduction was only a consequence of clinical improvement with Sacubitril/Valsartan or an anti-inflammatory effect is also present should be further evaluated.