Valor pronóstico de la función del ventrículo derecho y la hipertensión pulmonar en pacientes con insuficiencia cardíaca crónica: estudio clínico y traslacional

[spa] La hipertensión pulmonar (HP) y la disfunción del ventrículo derecho (VD) son dos factores pronósticos independientes en pacientes con insuficiencia cardíaca (IC). Las hipótesis de esta tesis son: 1) la disfunción del VD, el grado de HP y el desacoplamiento del VD-arteria pulmonar (AP) en pacientes con IC crónica progresan con el tiempo y esta evolución tiene un valor pronóstico; 2) el sildenafilo podría tener un efecto beneficioso sobre la función del VD; 3) el bosentan para el tratamiento de la HP post- trasplante cardíaco (TxC) es seguro y reduciría la disfunción del VD. Aproximadamente la mitad de los pacientes visitados por primera vez en una unidad de IC comunitaria tienen HP, disfunción ventricular derecha y un desacoplamiento VD-AP grave. En pacientes con IC avanzada candidatos a TxC la prevalencia de HP se mantiene en un 50%, mientras que la mayoría tiene algún grado de disfunción ventricular derecha, siendo grave en un 67%. En una cohorte de pacientes con IC crónica, en un seguimiento a largo plazo (15 años) se observa una progresión en forma de U de la presión arterial pulmonar (PAP) sistólica con nadir a los 7 años, mientras que la excursión sistólica del anillo tricuspideo (TAPSE) y el ratio TAPSE/PAP sistólica presentan un incremento durante el primer año para permanecer posteriormente estables, presentando el ratio un suave y progresivo descenso hacia el final. La HP y disfunción ventricular derecha confieren un mal pronóstico en la IC crónica, incrementando las hospitalizaciones por IC y la mortalidad. La presencia de HP y disfunción del VD basalmente duplica el riesgo de mortalidad y la permanencia de ambas entidades al año de seguimiento lo quintuplica. En pacientes con IC avanzada candidatos a TxC la disfunción ventricular derecha grave y los cambios en la fracción de eyección del VD (FEVD) a los seis meses se asocian con el riesgo de muerte en lista y necesidad de TxC urgente. Los dos parámetros ecocardiográficos que mejor correlacionan con la disfunción ventricular derecha grave medida por resonancia magnética cardíaca o tomografía computarizada cardíaca son el TAPSE y el cambio de área fraccional del VD. En un modelo experimental porcino de HP postcapilar el sildenafilo se asocia con una mejoría de la FEVD y del acoplamiento VD-AP, independiente de la postcarga, asociado con menor apoptosis, menor estrés oxidativo y menor inflamación en el miocardio del VD. El uso de bosentan en el post-TxC inmediato bajo supervisión estricta es seguro y puede ser eficaz para reducir el riesgo de fracaso agudo del injerto.[eng] Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are two independent prognostic factors in patients with heart failure (HF). The hypotheses of this thesis are: 1) RV dysfunction, the degree of PH, and RV-pulmonary artery (PA) uncoupling in patients with chronic HF progress over time and this evolution has a prognostic value; 2) sildenafil could have a beneficial effect on RV function; 3) bosentan for the treatment of PH in post-heart transplantation (HT) is safe and would reduce RV dysfunction. Approximately half of the patients visited for the first time in a community HF unit have PH, RV dysfunction, and severe RV-PA uncoupling. In patients with advanced HF who are candidates for HT, the prevalence of PH remains at 50%, while most have some degree of RV dysfunction, being severe in 67%. In a cohort of patients with chronic HF, in a long-term follow-up (15 years), a U-shaped progression of systolic pulmonary arterial pressure (PAP) with nadir at 7 years was observed, while the systolic excursion of the ring tricuspid (TAPSE) and the TAPSE/systolic PAP ratio show an increase during the first year to remain stable thereafter, the ratio showing a smooth and progressive decrease towards the end. PH and RV dysfunction confer a poor prognosis in chronic HF, increasing hospitalizations for HF and mortality. The presence of PH and RV dysfunction at baseline doubles the risk of mortality and the permanence of both entities at one year of follow-up increases the risk five times. In patients with advanced HF who are candidates for HT, severe RV dysfunction and changes in RV ejection fraction (RVEF) at six months are associated with the risk of death on the waiting list and the need for emergent HT. The two echocardiographic parameters that best correlate with severe RV dysfunction as measured by cardiac magnetic resonance imaging or cardiac computed tomography are TAPSE and RV fractional area change. In a porcine experimental model of postcapillary PH, sildenafil is associated with an improvement in RVEF and RV-PA coupling, independent of afterload, associated with less apoptosis, less oxidative stress and less inflammation in the RV myocardium. The use of bosentan in immediate post-HT under close supervision is safe and may be effective in reducing the risk of acute graft failure

Determination of HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in heart failure patients

Altres ajuts: Fundació La MARATÓ de TV3 (201502, 201516).Altres ajuts: PERIS/SLT002-16-00234Altres ajuts: PERIS/SLT002-16-00209Aims: Cell therapy can be used to repair functionally impaired organs and tissues in humans. Although autologous cells have an immunological advantage, it is difficult to obtain high cell numbers for therapy. Well-characterized banks of cells with human leukocyte antigens (HLA) that are representative of a given population are thus needed. The present study investigates the HLA allele and haplotype frequencies in a cohort of heart failure (HF) patients. Methods and results: We carried out the HLA typing and the allele and haplotype frequency analysis in 247 ambulatory HF patients. We determined HLA class I (A, B, and C) and class II (DRB1 and DQB1) using next-generation sequencing technology. The allele frequencies were obtained using Python for Population Genomics (PyPop) software, and HLA haplotypes were estimated using HaploStats. A total of 30 HLA-A, 56 HLA-B, 23 HLA-C, 36 HLA-DRB1, and 15 HLA-DQB1 distinct alleles were identified within the studied cohort. The genotype frequencies of all five HLA loci were in Hardy-Weinberg equilibrium. We detected differences in HLA allele frequencies among patients when the etiological cause of HF was considered. There were a total of 494 five-loci haplotypes, five of which were present six or more times. Moreover, the most common estimated HLA haplotype was HLA-A*01:01, HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, and HLA-DQB1*02:01 (6.07% haplotype frequency per patient). Remarkably, the 11 most frequent haplotypes would cover 31.17% of the patients of the cohort in need of allogeneic cell therapy. Conclusions: Our findings could be useful for improving allogeneic cell administration outcomes without concomitant immunosuppression

Gender-Related Differences in Heart Failure Biomarkers

Important differences in comorbidities and clinical characteristics exist between women and men with heart failure (HF). In particular, differences in the kinetics of biological circulating biomarkers-a critical component of cardiovascular care-are highly relevant. Most circulating HF biomarkers are assessed daily by clinicians without taking sex into account, despite the multiple gender-related differences observed in plasma concentrations. Even in health, compared to men, women tend to exhibit higher levels of natriuretic peptides and galectin-3 and lower levels of cardiac troponins and the cardiac stress marker, soluble ST2. Many biological factors can provide a reliable explanation for these differences, like body composition, fat distribution, or menopausal status. Notwithstanding, these sex-specific differences in biomarker levels do not reflect different pathobiological mechanisms in HF between women and men, and they do not necessarily imply a need to use different diagnostic cut-off levels in clinical practice. To date, the sex-specific prognostic value of HF biomarkers for risk stratification is an unresolved issue that future research must elucidate. This review outlines current evidence regarding gender-related differences in circulating biomarkers widely used in HF, the pathophysiological mechanisms underlying these differences, and their clinical relevance

Cardiovascular disease and COVID-19 : les liaisons dangereuses

Patients with cardiovascular risk factors or established cardiovascular disease have an increased risk of developing coronavirus disease 19 and have a worse outcome when infected, but translating this notion into effective action is challenging. At present it is unclear whether cardiovascular therapies may reduce the likelihood of infection, or improve the survival of infected patients. Given the crucial importance of this issue for clinical cardiologists and all specialists dealing with coronavirus disease 19, we tried to recapitulate the current evidence and provide some practical recommendations

Destination Therapy with Left Ventricular Assist Devices in Non-transplant Centres: The Time is Right

For almost half a century, cardiac transplant has been the only long-term treatment for patients with end-stage heart failure. Implantable left ventricular assist devices (LVADs) have emerged as a new treatment option for advanced heart failure as destination therapy for patients either too old or not suitable for transplant. A meta-analysis presenting head-to-head comparisons of cardiac transplant versus LVAD as destination therapy (LVAD-DT) found no difference in 1-year mortality rates between LVAD-DT and cardiac transplant (OR 1.49; 95% CI [0.48–4.66]; I2=82.8%). Moreover, a recent subanalysis from the Interagency Registry for Mechanically Assisted Circulatory Support found similar outcomes after LVAD-DT implantation in both transplant and non-transplant centres. The time is right for LVAD-DT in non-transplant centres, provided multidisciplinary heart failure teams and expertise are in place

Heart failure with preserved ejection fraction infrequently evolves toward a reduced phenotype in long-term survivors: a long-term prospective longitudinal study

Long-term trajectories of left ventricular ejection fraction (LVEF) in heart failure (HF) patients with preserved EF (HFpEF) remain unclear. Our objective was to assess long-term longitudinal trajectories in consecutive HFpEF patients and the prognostic impact of LVEF dynamic changes over time.Consecutive ambulatory HFpEF patients admitted to a multidisciplinary HF Unit were prospectively evaluated by 2-dimensional echocardiography at baseline and at 1, 3, 5, 7, 9, and 11 years of follow-up. Exclusion criteria were patients having a previous known LVEF <50%, patients undergoing only 1 echocardiogram study, and those with a diagnosis of dilated, noncompaction, alcoholic, or toxic cardiomyopathy. One hundred twenty-six patients (age, 71±13 years; 63% women) were included. The main pathogeneses were valvular disease (36%) and hypertension (28%). Atrial fibrillation was present in 67 patients (53%). The mean number of echocardiographies performed was 3±1.2 per patient. Locally weighted error sum of squares curves showed a smooth decrease of LVEF during the 11-year follow-up that was statistically significant in linear mixed-effects modeling (P=0.01). Ischemic patients showed a higher decrease than nonischemics. The great majority (88.9%) of patients remained in the HFpEF category during follow-up; 9.5% evolved toward HF with midrange LVEF, and only 1.6% dropped to HF with reduced LVEF. No significant relationship was found between LVEF dynamics in the immediate preceding period and mortality.LVEF remained =50% in the majority of patients with HFpEF for =11 years. Only 1.6% of patients evolved to HF with reduced LVEF. Dynamic LVEF changes were not associated with mortality.Peer ReviewedPostprint (author's final draft

Quality of life in patients with heart failure and improved ejection fraction : one-year changes and prognosis

The criteria for patients with heart failure (HF) and improved ejection fraction (HFimpEF) are a baseline left ventricular ejection fraction (LVEF) ≤40%, a ≥10-point increase from baseline LVEF, and a second LVEF measurement >40%. We aimed to (i) assess patients with HF and reduced LVEF (HFrEF) at baseline and compare quality of life (QoL) changes between those that fulfilled and those that did not fulfil the HFimpEF criteria 1 year later and (ii) assess the prognostic role of QoL in patients with HFimpEF. We reviewed data from a prospective registry of real-world outpatients with HF that were assessed for LVEF and QoL at a first visit to the HF clinic and 1 year later. QoL was evaluated with the Minnesota Living with Heart Failure Questionnaire (MLWHFQ). The primary prognostic endpoint was the composite of all-cause death or HF hospitalization. Baseline and 1-year LVEF and MLWFQ scores were available for 1040 patients with an initial LVEF ≤40% (mean age, 65.2 ± 11.7 years; 75.9% men). The main aetiology was ischaemic heart disease (52.9%), and patients were mostly in New York heart Association Classes II (71.1%) and III (21.6%). At baseline, the mean LVEF was 28.5% ± 7.3, and the mean MLWHFQ score was 30.2 ± 19.5. After 1 year, the mean LVEF increased to 38.0% ± 12.2, and the MLWHFQ scores improved to 17.4 ± 16.0. In 361 patients that fulfilled the HFimpEF criteria (34.7%), significant improvements were observed in both LVEF (from 28.7% ± 6.6 to 50.9% ± 7.6, P < 0.001) and QoL (from 32.9 ± 20.6 to 16.9 ± 16.0, P < 0.001). Patients that did not fulfil the HFimpEF criteria also showed significant improvements in LVEF (from 28.4% ± 7.6 to 31.1% ± 7.9, P < 0.001) and QoL (from 28.7 ± 18.8 to 17.6 ± 15.9, P < 0.001). However, the QoL improvement was significantly higher in the HFimpEF group (−16.0 ± 23.8 vs. −11.1 ± 20.3, P = 0.001), despite the worse mean baseline MLWHFQ score, compared with the non-HFimpEF group (P = 0.001). The 1-year QoL was similar between groups (P = 0.50). The 1-year MLWHFQ score was independently associated with outcomes; the hazard ratio for the composite endpoint was 1.02 (95% CI: 1.01-1.03, P = 0.006). In contrast, the QoL improvement (with a cut-off ≥5 points) was not independently associated with the composite outcome. Patients with HFrEF showed improved QoL after 1 year, regardless of whether they met the HFimpEF criteria. The similar 1-year QoL perception between groups suggested that factors other than LVEF influenced QoL perception. The 1-year QoL was superior to the QoL change from baseline for predicting prognosis in patients with HFimpEF

Mortality trends in an ambulatory multidisciplinary heart failure unit from 2001 to 2018

To assess mortality trends at 1 and 3 years from 2001 to 2018 in a real-life cohort of HF outpatients from different etiologies with depressed and preserved LVEF. A total of 2368 consecutive patients with HF (mean age 66.4 ± 12.9 years, 71% men, 15.4% with preserved LVEF) admitted to a HF clinic from August 2001 to September 2018 were included in the study. Patients were divided into five quintiles (Q) according to the period of admission. Trends for all-cause and cardiovascular mortality from Q1 to Q5 were assessed by linear regression. Patients with LVEF < 50% had a progressive decrease in the rates of all-cause and cardiovascular death at 1 year (12.1% in Q1 to 6.5% in Q5, p = 0.003; and 8.4% in Q1 to 3.8% in Q5, p = 0.007, respectively) and 3 years (30.5% in Q1 to 17.0% in Q5, p = 0.003; and 23.9% in Q1 to 9.8% in Q5, p = 0.003, respectively). These trends remained significant after adjusting for clinical characteristics and risk. No significant trend in mortality was observed in patients with LVEF ≥ 50%. In a cohort of real-life ambulatory patients with HF, mortality progressively declined in patients with LVEF < 50%, but the same trend was not observed in patients with preserved LVEF

Long-term LVEF trajectories in patients with type 2 diabetes and heart failure : diabetic cardiomyopathy may underlie functional decline

Left ventricular ejection fraction (LVEF) trajectories and functional recovery with current heart failure (HF) management is increasingly recognized. Type 2 diabetes mellitus (T2D) leads to a worse prognosis in HF patients. However, it is unknown whether T2D interferes with LVEF trajectories. The aim of this study was to prospectively assess very long-term (up to 15 years) LVEF trajectories in patients with and without T2D and underlying HF. Ambulatory patients admitted to a multidisciplinary HF clinic were prospectively evaluated by scheduled two-dimensional echocardiography at baseline, 1 year, and then every 2 years afterwards, up to 15 years. Statistical analyses of LVEF change with time were performed using the linear mixed effects (LME) models, and locally weighted error sum of squares (Loess) curves were plotted. Of the 1921 patients, 461 diabetic and 699 non-diabetic patients with LVEF < 50% were included in the study. The mean number of echocardiography measurements performed in diabetic patients was 3.3 ± 1.6. Early LVEF recovery was similar in diabetic and non-diabetic patients, but Loess curves showed a more pronounced inverted U shape in diabetics with a more pronounced decline after 9 years. LME analysis showed a statistical interaction between T2D and LVEF trajectory over time (p = 0.009), which was statistically significant in patients with ischemic etiologies (p < 0.001). Other variables that showed an interaction between LVEF trajectories and T2D were male sex (p = 0.04) and HF duration (p = 0.008). LVEF trajectories in T2D patients with depressed systolic function showed a pronounced inverted U shape with a marked decline after 9 years. Diabetic cardiomyopathy may underlie the functional decline observed

Unraveling the Molecular Mechanism of Action of Empagliflozin in Heart Failure With Reduced Ejection Fraction With or Without Diabetes

The mechanism of action of empagliflozin in heart failure with reduced ejection fraction (HFrEF) was deciphered using deep learning in silico analyses together with in vivo validation. The most robust mechanism of action involved the sodium-hydrogen exchanger (NHE)-1 co-transporter with 94.7% accuracy, which was similar for diabetics and nondiabetics. Notably, direct NHE1 blockade by empagliflozin ameliorated cardiomyocyte cell death by restoring expression of X-linked inhibitor of apoptosis (XIAP) and baculoviral IAP repeat-containing protein 5 (BIRC5). These results were independent of diabetes mellitus comorbidity, suggesting that empagliflozin may emerge as a new treatment in HFrEF.S