Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial.

Importance: Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies. Objective: To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF. Design, Setting, and Participants: Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted. Patients were randomized in a 2:1 ratio (omecamtiv mecarbil to placebo) between March 2019 and May 2021 at 63 sites in North America and Europe, with the last patient visit occurring on November 29, 2021. Interventions: Omecamtiv mecarbil (n = 185) or matching placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels, for 20 weeks. Main Outcomes and Measures: The primary end point was a change in exercise capacity (peak V̇o2) from baseline to week 20. Secondary end points included total workload, ventilatory efficiency, and daily physical activity as determined by accelerometry. Results: Among 276 patients who were randomized (median age, 64 years; IQR, 55-70 years; 42 women [15%]), 249 (90%) completed the trial. The median left ventricular ejection fraction was 28% (IQR, 21-33) and the median baseline peak V̇o2 was 14.2 mL/kg/min (IQR, 11.6-17.4) in the omecamtiv mecarbil group and 15.0 mL/kg/min (IQR, 12.0-17.2) in the placebo group. Mean change in peak V̇o2 did not differ significantly between the omecamtiv mecarbil and placebo groups (mean, -0.24 mL/kg/min vs 0.21 mL/kg/min; least square mean difference, -0.45 mL/kg/min [95% CI, -1.02 to 0.13]; P = .13). Adverse events included dizziness (omecamtiv mecarbil: 4.9%, placebo: 5.5%), fatigue (omecamtiv mecarbil: 4.9%, placebo: 4.4%), heart failure events (omecamtiv mecarbil: 4.9%, placebo: 4.4%), death (omecamtiv mecarbil: 1.6%, placebo: 1.1%), stroke (omecamtiv mecarbil: 0.5%, placebo: 1.1%), and myocardial infarction (omecamtiv mecarbil: 0%, placebo: 1.1%). Conclusions and Relevance: In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo. These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT03759392.

Breakthroughs in the treatment of heart failure with mildly reduced and preserved ejection fraction.

Historically, only patients with a left ventricular ejection fraction (LVEF) of less than or equal to 40% were considered to have heart failure (HF). However, it was later found that patients could have elevated cardiac filling pressures and the stigmata of HF signs and symptoms with normal LVEF. This subset of patients has undergone multiple taxonomical variations and is now termed heart failure with preserved ejection fraction (HFpEF) with the lower limit of LVEF assigned as roughly ≥40%-50% in clinical trials and ≥50% in HF guidelines. Patients with LVEF 41%-49% did not clearly fit these designations but bear resemblance to both heart failure with reduced ejection fraction (HFrEF) and HFpEF. This cohort was initially assigned the term HFpEF (borderline), which has also undergone several modifications and is currently termed heart failure with mildly reduced ejection fraction (HFmrEF). Earlier landmark HF trials were heavily focused on patients with HFrEF. Only in the last 2 decades has there been an increasing focus on HFpEF with emergence of key drug therapies including sodium-glucose cotransport-2 inhibitors that have shown to improve outcomes across the whole LVEF spectrum. There is yet to be a focused clinical trial to determine therapeutic modalities for HFmrEF; most of the evidence has been extrapolated from subgroup analysis mostly from HFpEF trials. In this review, we provide an overview of the historical basis of HFpEF and HFmrEF and discuss key therapeutic advances in their management.

The Role of the Immune System on the Cardiac Complications Observed in SARS-CoV-2

Abstract An acute respiratory syndrome caused by SARS-CoV2 was declared a pandemic by the World Health Organization. Current data in the world and in Brazil show that approximately 40% of patients who died have some type of cardiac comorbidity. There are also robust reports showing an increase in IL-6 / IL-1B / TNF-alpha and the presence of lymphopenia in patients with COVID-19. Our team and others have shown that increased cytokines are the link between arrhythmias/Left ventricular dysfunction and the immune system in different diseases. In addition, it has been well demonstrated that lymphopenia can not only be a good marker, but also a factor that causes heart failure. Thus, the present review focused on the role of the immune system upon the cardiac alterations observed in the SARS-CoV2 infection. Additionally, it was well described that SARS-CoV-2 is able to infect cardiac cells. Therefore, here it will be reviewed in deep.

Correlation of serum ST2 levels with severity of diastolic dysfunction on echocardiography and findings on cardiac MRI in patients with heart failure with preserved ejection fraction.

OBJECTIVE: The aim of the present study was to find a correlation of serum Suppression of tumorigenicity 2 (ST2) levels with severity of diastolic dysfunction on echocardiography and cardiac magnetic resonance imaging (CMRI) in heart failure with preserved ejection fraction (HFpEF) patients. METHODS: Fifty patients aged ≥18 years fulfilling diagnostic criteria for HFpEF were included. ST2 levels, 2D echocardiography and CMRI were performed. Left ventricular ejection fraction, E/A, Septal E/E', left atrial volume index (LAVI), tricuspid regurgitation (TR), assessment of diastolic dysfunction, T1 mapping in milliseconds and late gadolinium enhancement (LGE) in percentage were noted. The primary outcome measure was to study correlation of ST2 levels with severity of diastolic dysfunction, whereas the secondary outcome measures were to study correlation of ST2 levels with native T1 mapping and LGE on CMRI. RESULTS: ST2 levels showed statistically significant and positive correlation with E/E' (r = 0.837), peak TR velocity (r = 0.373), LAVI (r = 0.74), E/A (r = 0.420), and T1 values in milliseconds (r = 0.619). There was no statistically significant correlation between ST2 level and LGE in % (r = 0.145). The median ST2 levels in patients with E/E' > 14 and E/E' ≤ 14 were 110.8 and 36.1 respectively (p-value < 0.05). The mean ST2 levels were significantly higher in patients who had diastolic dysfunction grade III (126.4) and New York Heart Association class IV (133.3). CONCLUSIONS: Evaluation of ST2 adds important information to support the diagnosis of left ventricular diastolic dysfunction in patients with HFpEF.

Perfil clínico y causas de muerte de los pacientes con insuficiencia cardíaca atendidos en una unidad especializada de Cardiología según su fracción de eyección / Clinical profile and causes of death according to ejection fraction in patients with heart failure cared for in a specialized Cardiology unit

Antecedente y objetivo: Los pacientes con insuficiencia cardíaca se caracterizan en 3 fenotipos en función de su fracción de eyección ventricular izquierda. El propósito de este estudio fue comparar el perfil clínico, el tratamiento, el pronóstico y las causas de muerte de los pacientes con insuficiencia cardíaca y fracción de eyección ventricular izquierda reducida (<40%, IC-FEr), preservada (≥50%, IC-FEp) o en rango medio (40-49%, IC-FErm). Metodología: Análisis de la información clínica recogida en un registro prospectivo de pacientes con insuficiencia cardíaca remitidos a una consulta monográfica de Cardiología entre 2010 y 2019. Resultados: Se estudiaron 1.404 pacientes con IC-FEr, 239 pacientes con IC-FErm y 266 pacientes con IC-FEp. Se observaron diferencias significativas entre los 3 grupos en relación con diversas características clínicas, y en cuanto a la tasa de prescripción de fármacos moduladores de la respuesta neurohormonal. La regresión de Cox multivariante reveló un incremento del riesgo de muerte por cualquier causa en los pacientes con IC-FEp (hazard-ratio 1,36; intervalo de confianza al 95% 1,03-1,80; p=0,028) e IC-FErm (hazard-ratio 1,36; intervalo de confianza al 95% 1,03-1,78; p=0,029) en comparación con los pacientes con IC-FEr. La insuficiencia cardíaca fue la causa más frecuente de muerte en los 3 grupos; se observó un mayor peso relativo de la muerte súbita en los pacientes con IC-FEr, mientras que las causas no cardiovasculares de muerte tuvieron un peso relativo mayor en los pacientes con IC-FEp e IC-FErm. Conclusiones: El estudio confirma la existencia de diferencias significativas en el perfil clínico, manejo terapéutico, pronóstico y causas de muerte de los pacientes con IC-FEr, IC-FErm e IC-FEp (AU)

Background and objective: Patients with heart failure are classified into three phenotypes based on left ventricular ejection fraction. This work aimed to compare the clinical profile, treatment, prognosis, and causes of death of patients with heart failure and reduced (<40%, HF-rEF), preserved (≥50%, HF-pEF), or mid-range (40–49%, HF-mrEF) left ventricular ejection fraction. Methods: An analysis was conducted on the clinical data included in a prospective registry of patients with heart failure who were referred to a specific Cardiology unit from 2010 to 2019. Results: A total of 1,404 patients with HF-rEF, 239 patients with HF-mrEF, and 266 patients with HF-pEF were analyzed. Significant differences were observed among the groups in regard to several clinical characteristics and the frequency of prescription of neurohormonal blocking drugs. A multivariate Cox regression revealed an increased risk of all-cause mortality in patients with HF-pEF (hazard ratio 1.36; 95% confidence interval 1.03-1.80; p=0.028) and patients with HF-mrEF (hazard ratio 1.36; 95% confidence interval 1.03–1.78; p=0.029) as compared to patients with HF-rEF. Heart failure was the most frequent cause of death in the three subgroups. A higher relative weight of sudden death as a cause of death was observed among patients with HF-rEF while the relative weight of non-cardiovascular causes of death was higher among patients with HF-pEF and HF-mrEF. Conclusions: This study confirms the existence of significant differences among patients with HF-rEF, HF-mrEF, and HF-pEF with regard to their clinical profile, therapeutic management, prognosis, and causes of death (AU)

Echocardiographic study of myocardial work in patients with type 2 diabetes mellitus.

BACKGROUND: A noninvasive left ventricular (LV) pressure-strain loop (PSL) provides a new method to quantify myocardial work (MW) by combining global longitudinal strain (GLS) and LV pressure, which exerts potential advantages over traditional GLS. We studied the LV PSL and MW in patients with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 201 subjects (54 healthy controls and 147 T2DM patients) who underwent complete two-dimensional echocardiography (2DE), including 2D speckle-tracking echocardiography (STE), as well as brachial artery pulse pressure measurement. The PSL was used to determine the global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) of all study participants. The association between T2DM and LV function was evaluated according to these MW indices. RESULTS: The GLS was significantly lower in the T2DM group than in the control group (P < 0.001), indicating that the LV myocardium had been damaged, although the LV ejection fraction (LVEF) was still normal. The GWI and GWE were decreased (P = 0.022) and the GWW was increased (P < 0.001) in diabetic patients compared with controls, but the GCW was comparable in the two groups (P = 0.160). In all diabetic patients, age, body mass index, systolic blood pressure, smoking history, and LVEF were correlated with GWI, GWW and GWE. CONCLUSIONS: The use of LV PSL is a novel noninvasive technique that could help to depict the relationship between LV myocardial damage and MW in patients with T2DM.

Left atrial reservoir strain improves diagnostic accuracy of the 2016 ASE/EACVI diastolic algorithm in patients with preserved left ventricular ejection fraction: insights from the KARUM haemodynamic database.

AIMS: This study aimed to investigate the incremental value offered by left atrial reservoir strain (LASr) to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) diastolic algorithm to identify elevated left ventricular (LV) filling pressure in patients with preserved ejection fraction (EF). METHODS AND RESULTS: Near-simultaneous echocardiography and right heart catheterization were performed in 210 patients with EF ≥50% in a large, dual-centre study. Elevated filling pressure was defined as invasive pulmonary capillary wedge pressure (PCWP) ≥15 mmHg. LASr was evaluated using speckle-tracking echocardiography. Diagnostic performance of the ASE/EACVI diastolic algorithm was validated against invasive reference and compared with modified algorithms incorporating LASr. Modest correlation was observed between E/e', E/A ratio, and LA volume index with PCWP (r = 0.46, 0.46, and 0.36, respectively; P < 0.001 for all). Mitral e' and TR peak velocity showed no association. The ASE/EACVI algorithm (89% feasibility, 71% sensitivity, 68% specificity) demonstrated reasonable ability (AUC = 0.69) and 68% accuracy to identify elevated LV filling pressure. LASr displayed strong ability to identify elevated PCWP (AUC = 0.76). Substituting TR peak velocity for LASr in the algorithm (69% sensitivity, 84% specificity) resulted in 91% feasibility, 81% accuracy, and stronger agreement with invasive measurements. Employing LASr as per expert consensus (71% sensitivity, 70% specificity) and adding LASr to conventional parameters (67% sensitivity, 84% specificity) also demonstrated greater feasibility (98% and 90%, respectively) and overall accuracy (70% and 80%, respectively) to estimate elevated PCWP. CONCLUSIONS: LASr improves feasibility and overall accuracy of the ASE/EACVI algorithm to discern elevated filling pressures in patients with preserved EF.

Factors Associated with Left Ventricular Function Recovery in Patients with Atrial Fibrillation Related Cardiomyopathy.

BACKGROUND: The diagnosis of atrial fibrillation (AFIB) related cardiomyopathy relies on ruling out other causes for heart failure and on recovery of left ventricular (LV) function following return to sinus rhythm (SR). The pathophysiology underlying this pathology is multifactorial and not as completely known as the factors associated with functional recovery following the restoration of SR. OBJECTIVES: To identify clinical and echocardiographic factors associated with LV systolic function improvement following electrical cardioversion (CV) or after catheter ablation in patients with reduced ejection fraction (EF) related to AFIB and normal LV function at baseline. METHODS: The study included patients with preserved EF at baseline while in SR whose LVEF had reduced while in AFIB and improved LVEF following CV. We compared patients who had improved LVEF to normal baseline to those who did not. RESULTS: Eighty-six patients with AFIB had evidence of reduced LV systolic function and improved EF following return to SR. Fifty-five (64%) returned their EF to baseline. Patients with a history of ischemic heart disease (IHD), worse LV function, and larger LV size during AFIB were less likely to return to normal LV function. Multivariant analysis revealed that younger patients with slower ventricular response, a history of IHD, larger LV size, and more significant deterioration of LVEF during AFIB were less likely to recover their EF to baseline values. CONCLUSIONS: Patients with worse LV function and larger left ventricle during AFIB are less likely to return their baseline LV function following the restoration of sinus rhythm.

The short term influence of right ventricular pacing burden on echocardiographic and spiroergometric parameters in patients with preserved left ventricular ejection fraction.

BACKGROUND: The incidence of worsened clinical outcome due to high right ventricular (RV) pacing burden in patients with preserved left ventricular function remains controversial. OBJECTIVE: To investigate the impact of RV pacing on several echocardiographic and spiroergometric parameters. METHODS: In 60 pacemaker patients with preserved left ventricular ejection fraction (LVEF) serial echocardiographies and spiroergometries were performed over a time course of 12 months. Additionally, in 48 patients retrospective echocardiographic analyses of the LV- and RV function were carried out up to 24 months after pacemaker implantation. RESULTS: The patients were divided into two groups: The high RV pacing burden group (hRVP: ≥ 40%) and the low RV pacing group (lRVP < 40%) according to the definitions in previous randomized MOST and DAVID trials. After a period of 12-month pacemaker therapy no changes to left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), LVEF, E/A-ratio; E/E'-ratio and tricuspid annular plane systolic excursion (TAPSE) could be revealed, independently of the RV pacing burden. Additionally, after 24-month long term follow-up there were no differences in LVEF and TAPSE in both groups. Accordingly, no relevant changes of peak exercise capacity, ventilatory anaerobic threshold or maximal oxygen consumption could be demonstrated independently of the RV pacing. CONCLUSIONS: In pacemaker patients with preserved LVEF the burden of RV pacing has no adverse influence on several echocardiographic and spiroergometric surrogate parameters of pacemaker-induced cardiomyopathy after a follow-up of 12 to 24 month. Despite this, screening for pacemaker induced cardiomyopathy should be performed especially in the presence of new heart failure symptoms.

High prevalence of occult left ventricular diastolic dysfunction detected by exercise stress test in systemic sclerosis.

Despite the poor prognosis of systemic sclerosis (SSc) due to the co-occurrence of left ventricular diastolic dysfunction (LVDD), presence of occult LVDD has not been sufficiently investigated. This retrospective study aimed to reveal the prevalence and determinants of occult LVDD in patients with SSc by exercise stress test. Forty-five SSc patients (age, 63 ± 13 years; men/women, 6/39) with normal pulmonary artery pressure and pulmonary artery wedge pressure (PAWP) at rest underwent a symptom-limited exercise test with right heart catheterization using a supine cycle ergometer; haemodynamic parameters at rest, leg raise and during exercise were evaluated. Occult LVDD defined PAWP ≥ 25 mmHg during exercise was seen in 13 patients (29%). Higher PAWP, lower pulmonary vascular resistance and diastolic pulmonary pressure gradient, larger left atrium at rest, and higher PAWP during leg raise (15 ± 4 vs 10 ± 4 mmHg in non-LVDD group, p < 0.001) were observed in the occult LVDD group. The area under the ROC curve for PAWP after leg raise was largest at 0.83 (95% CI: 0.70-0.95, p = 0.001). About one-third (29%) of SSc patients with normal haemodynamics at rest showed occult LVDD. A higher PAWP after leg raise could be useful for detecting occult LVDD.

Diastolic dysfunction in people with HIV without known cardiovascular risk factors in Western Kenya.

OBJECTIVES: Diastolic dysfunction (DD) has been reported to be highly prevalent in people living with HIV (PLWH) on antiretroviral therapy (ART) leading to the hypothesis that it may be an early marker of myocardial disease. Our objective was to evaluate the prevalence of DD in people living with human immunodeficiency virus without known history of diabetes or hypertension in Western Kenya. METHODS: In this cross-sectional study in western Kenya, 110 PLWH on ART and without known diabetes or hypertension were matched for age ±5 years and sex to HIV-uninfected controls. Study participants underwent a comprehensive two-dimensional echocardiogram and laboratory testing. RESULTS: The mean (SD) age in the HIV-positive group was 42.9 (8.6) years compared with 42.1 (12.9) years in the HIV-uninfected group. Mean (SD) CD4 +T cell count for the HIV-positive group was 557 (220) cells/ml. Mean systolic and diastolic blood pressures were within the normal range and comparable between the two groups. Mean body mass index was 25.2 (5.4) kg/m2 and 26.3 (5.4) kg/m2 in HIV-positive and uninfected participants, respectively. There was only 1 (0.9 %) case of DD in each group. Despite low prevalence of DD, PLWH had 5.76 g/m2 higher left ventricular mass index (p=0.01) and 2.77 mL/m2 larger left atrial volume (p=0.02) compared with the HIV-negative group after adjusting for risk factors associated with DD. CONCLUSION: Contrary to prior reports, DD in PLWH was low. Environmental and cardiovascular disease risk factors such as diabetes and hypertension may be significant modifiers for development and progression of DD in PLWH.