Carboximaltosa férrica en pacientes con insuficiencia cardíaca con fracción de eyección reducida y deficiencia de hierro previo cirugía cardiovascular / Ferric carboxymaltose in patients with heart failure with reduced exercise fraction and iron deficiency before cardiovascular surgery

ÁREA DESCRIPTIVA DEL PROBLEMA DE SALUD: Definición: La anemia y la ferropenia son dos importantes comorbilidades comunes en pacientes con Insuficiencia Cardíaca (IC) y se asocian a un mal estado clínico y a peores resultados a corto y largo plazo; la anemia y la ferropenia son de hecho, medidores de pobre pronóstico en pacientes con IC, corregir estas comorbilidades sería una diana terapéutica atractiva y novedosa para mejorar los resultados. La anemia se asocia de forma independiente con la gravedad de la IC y la mortalidad, y la deficiencia de hierro parece asociarse de forma exclusiva con una menor capacidad de ejercicio. La deficiencia de hierro suele definirse como un nivel de ferritina <100 µg /L o un nivel de 100 a 300 µg/L, si la saturación de transferrina es <20%. Se ha demostrado que la repleción intravenosa de hierro mejora la capacidad de ejercicio y la calidad de vida. Principales manifestaciones clínicas: la identificación de los síntomas es un paso clave en el diagnóstico; estos incluyen aquellos relacionados a la sobrecarga hídrica (disnea, ortopnea, edema, dolor por la congestión hepática, y discomfort abdominal asociado a la distensión por la ascitis) y aquellos secundarios a la reducción del gasto cardíaco (debilidad, fatiga) que se pronuncian más con el ejercicio.(2) En cuanto a la anemia, definida como la reducción de 1 o más componentes de la línea roja celular (concentración de hemoglobina, hematocrito, o conteo de glóbulos rojos) una concentración baja de hemoglobina o bajo hematocrito son los parámetros ampliamente usados para el diagnóstico, con los siguientes rangos. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas Pubmed Carboximaltosa férrica; Insuficiencia cardiaca; Deficiencia de hierro; Hierro Sacarosa; Anemia; cirugía cardiovascular. Se filtra la búsqueda a Estudios Clínicos fase 111, controlados randomizados, Revisiones Sistemáticas, Meta-análisis, Guías de Práctica Clínica, además se limitó la búsqueda estudios en humanos. También se realiza búsqueda manual en otras bases de datos bibliográficas (Cochrane, NIH, TRIP 0ATABASE), en buscadores genéricos de internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas, meta-análisis, estudios clínicos aleatorizados y controlados, guías de práctica clínica, evaluaciones de tecnología sanitaria, evaluaciones económicas y políticas de cobertura de otros sistemas de salud. CONCLUSIONES. Eficacia: Carboximaltosa Férrica es un medicamento propuesto para el tratamiento de pacientes con anemia por déficit de hierro, en quienes no se puede corregir esta afección con hierro oral, o se necesita hacerlo de una manera rápida; La evaluación de este efecto se ha hecho a través de ensayos clínicos controlados y aleatorizados. Estos estudios sugieren que el uso de carboximaltosa férrica puede ser eficaz para corregir la anemia secundaria por déficit de hierro, pero es importante recalcar que los estudios pivotales están hechos comparando su uso con placebo; la utilización se asocia con mejoría en la calidad de vida de estos pacientes y menos tiempo de estancia hospitalaria; sin embargo, estos mismos informes refieren que no hay disminución en la probabilidad de muerte en general para estos pacientes; es muy importante mencionar que a pesar de que la carboximaltosa férrica al momento está siendo muy estudiada para el uso de pacientes con déficit de hierro e insuficiencia cardíaca, los preparados como Hierro Sacarosa también han sido estudiados en esta patología , y faltan más investigaciones donde se comparen estos dos preparados para obtener mayor evidencia sobre el beneficio de usar uno sobre el otro; además, también hay una gran falta de estudios específicos sobre la población preoperatoria que se someterá a cirugía cardiovascular; si bien es cierto se hace un especial énfasis acerca de la importancia de identificar y corregir la anemia preoperatoria, las guías clínicas actualizadas y revisiones de la literatura no especifican a la carboximaltosa férrica como medicamento de primera línea en el manejo de los pacientes sometidos a cirugía cardiovascular. También, es de hacer notar que la mayoría de investigaciones se han realizado en poblaciones específicas que no pueden ser generalizados a otras poblaciones, así como hay heterogeneidad en los parámetros estudiados entre ellos como los valores de hemoglobina en cada estudio siendo un dato importante para esta revisión. Seguridad: De acuerdo a la revisión realizada se puede concluir que la administración de Carboximaltosa férrica es segura; La reacción adversa reportada con mayor frecuencia fue náuseas (que se produce en el 3,2% de los sujetos), seguida por reacciones en el lugar de inyección/perfusión, hipofosfatemia, cefalea, rubefacción, mareos e hipertensión. Las reacciones en el lugar de inyección/perfusión se componen de varias reacciónes adversas que de forma individual son poco frecuentes o raras. La más grave es la reacción anafiláctica (rara); se han notificado muertes con su uso; los estudios también demuestran que ambas terapias presentan reacciones similares, siendo las más comunes los trastornos de hipersensibilidad, gastrointestinales y desequilibrios hidroelectrolíticos. Aunque es cierto que la literatura describe un ligero aumento en la frecuencia de estas reacciones con Hierro Sacarosa, también se menciona que la mayoría de ellas son rápidamente reversibles y no ponen en peligro la vida de los pacientes. Costo: Para el ISSS, el uso de Carboximaltosa Férrica en pacientes con Insuficiencia Cardíaca y anemia podría considerarse una opción rentable a largo plazo. Dado que se requiere una única aplicación y menos personal y espacio hospitalario, el costo de adquisición se puede recuperar a través de la reducción de recursos de salud utilizados y la ocupación de camas hospitalarias. Aunque al comparar el costo de adquisición de este medicamento con Hierro Sacarosa, un medicamento ya disponible en la institución, se observa que, a pesar de que se necesitan dosis mayores de Hierro Sacarosa para lograr el mismo efecto, el costo total de estas dosis no supera la aplicación individual de Carboximaltosa Férrica. Conveniencia: A pesar de lo antes mencionado sobre el beneficio del uso de carboximaltosa de hierro, en pacientes con déficit de hierro e insuficiencia cardíaca; La mayoría de documentos mencionan que el hierro intravenoso podría controlar los niveles de hemoglobina en los pacientes sometidos a cirugía electiva, no está clara la repercusión del hierro intravenoso sobre los resultados (transfusiones sanguíneas, riesgo de infecciones, o supervivencia en general). En la institución se cuenta con Hierro Sacarosa, un preparado endovenoso que también se utiliza para la corrección de la anemia por déficit de hierro; las ventajas que se presentan de la carboximaltosa férrica a este preparado se centran en menor número de dosis y menor estancia hospitalaria, que se traducen en menor uso de recursos y menor tiempo cama hospitalaria; sin embargo, no hay estudios que prueben el beneficio en una rápida corrección de hemoglobina utilizando carboximaltosa férrica sobre hierro sacarosa, por lo que no es posible concluir que sea más conveniente su uso en pacientes preoperatorios que necesiten un rápido restablecimiento de estos valores.

Dilemas de la insuficiencia cardíaca con fracción de eyección preservada / Dilemmas of heart failure with preserved ejection fraction / Dilemas da insuficiência cardíaca com fração de ejeção preservada

La insuficiencia cardíaca con fracción de eyección preservada (ICFEp) y reducida presentan marcadas diferencias. Mientras que la última tiene un algoritmo diagnóstico y terapéutico desde hace años, con guías y fármacos que mejoran su pronóstico, la ICFEp no solo presenta dificultades para llegar al diagnóstico, sino que tampoco hay fármacos que hayan demostrado disminuir la mortalidad. En esta revisión se hace un abordaje amplio de la ICFEp, comenzando por definirla y distinguirla de la disfunción diastólica. Se describe el gold standard para su diagnóstico invasivo y se analizan los scores no invasivos recientemente desarrollados que estiman la probabilidad de tener la enfermedad. A través del análisis de las comorbilidades frecuentemente asociadas, se describen los mecanismos fisiopatológicos implicados. Asimismo, se detallan los fenotipos propuestos para agrupar pacientes y diseñar ensayos clínicos con fármacos que prueben disminuir la mortalidad. Por último, se reseñan las medidas terapéuticas no farmacológicas y farmacológicas recomendadas.

Heart failure with preserved and reduced ejection fraction have significant differences. While the latter has had a diagnostic and therapeutic algorithm for years, with guidelines and drugs that improve its prognosis, heart failure with preserved ejection fraction (HFpEF) not only presents difficulties in reaching a diagnosis, but also there are no drugs that have been proven to be effective in reducing mortality. In this review, a broad approach to HFpEF is made, beginning by defining it and distinguishing it from diastolic dysfunction. The gold standard for its invasive diagnosis is described and recently developed non-invasive scores that estimate the probability of having the disease are analyzed. Through the analysis of the frequently associated comorbidities, the pathophysiological mechanisms involved are described. Likewise, the phenotypes proposed to group patients and design clinical trials with drugs that try to reduce mortality are detailed. Finally, the recommended non-pharmacological and pharmacological therapeutic measures are outlined.

A insuficiência cardíaca com fração de ejeção preservada (ICFEp) e reduzida apresentam diferenças marcantes. Enquanto esta última conta com um algoritmo diagnóstico e terapêutico há anos, com diretrizes e medicamentos que melhoram seu prognóstico, a ICFEp não só apresenta dificuldades no diagnóstico, mas nenhum há medicamentos que tenham demonstrado reduzir a mortalidade. Nesta revisão, é feita uma abordagem ampla da ICFEp, começando por defini-la e distinguindo-a da disfunção diastólica. O padrão ouro para seu diagnóstico invasivo é descrito e são analisados os escores não invasivos recentemente desenvolvidos que estimam a probabilidade de ter a doença. Através da análise de comorbidades frequentemente associadas, são descritos os mecanismos fisiopatológicos envolvidos. Da mesma forma, são detalhados os fenótipos propostos para agrupar pacientes e desenhar ensaios clínicos com medicamentos que podem ser mostradas para reduzir a mortalidade. Por fim, são delineadas as medidas terapêuticas não farmacológicas e farmacológicas recomendadas.

Retrospective Study of 573 Patients with Heart Failure Evaluated for Coronary Artery Disease at Toulouse University Center, France.

BACKGROUND Heart failure (HF) most commonly occurs due to ischemic heart disease from stenotic coronary artery disease (CAD). HF is classified into 3 groups based on the percentage of the ejection fraction (EF): reduced (HFrEF), mid-range (HFmrEF), and preserved (HFpEF). This retrospective study included 573 patients who presented with HF based on the evaluation of EF and were evaluated for CAD by coronary angiography before undergoing coronary angioplasty at a single center in Toulouse, France. MATERIAL AND METHODS This retrospective observational study included patients recently diagnosed with HF or acute decompensation of chronic HF and referred for coronary angiography at Toulouse University Hospital between January 2019 and May 2020. RESULTS Significant CAD was found in 55.8%, 55%, and 55% of the whole population, HFpEF, and HFrEF groups, respectively. Older age, male sex, and diabetes mellitus were the main risk factors for ischemic HF. Except for age and sex, patients with ischemic HFpEF were comparable to those with non-ischemic HFpEF, unlike the ischemic HFrEF group, which had more common cardiovascular risk factors than the non-ischemic HFrEF group. The ischemic HFpEF group had an older age and higher rate of dyslipidemia than the ischemic HFrEF group. CONCLUSIONS At our center, CAD was diagnosed in more than half of patients who presented with heart failure with preserved or reduced EF. Older age and male sex were the common risk factors in patients with HFpEF and HFrEF.

The vasculature: a therapeutic target in heart failure?

It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.

Diastolic and systolic left ventricular dysfunction and mortality in chronic kidney disease patients on haemodialysis.

AIMS: Left ventricular diastolic dysfunction (LVDD) and LV systolic dysfunction (LVSD) are prevalent in CKD, but their prognostic relevance is debatable. We intent to verify whether LVDD and LVSD are independently predictive of all-cause mortality and if they have comparable or different effects on outcomes. METHODS: A retrospective analysis was conducted of the echocardiographic data of 1285 haemodialysis patients followed up until death or transplantation. LVDD was classified into 4 grades of severity. Endpoint was all-cause mortality. RESULTS: During a follow-up of 30 months, 419/1285 (33%) patients died, 224 (53%) due to CV events. LVDD occurred in 75% of patients, grade 1 DD was the prevalent diastolic abnormality, and pseudonormal pattern was the predominant form of moderate-severe DD. Moderate-severe LVDD (HR 1.379, CI% 1.074-1.770) and LVSD (HR 1.814, CI% 1.265-2.576) independently predicted death; a graded, progressive association was found between LVDD categories and the risk of death; and the impact of isolated severe-moderate LVDD on the risk of death was comparable to that exercised by isolated compromised LV systolic function. CONCLUSION: Moderate-severe LVDD and LVSD were independently associated with a higher probability of death and had a similar impact on survival. A progressive association was observed between LVDD grades and mortality.

Outcomes of Patients With Diabetes Versus Patients Without Diabetes Hospitalized With Acute Heart Failure.

The objective is to define the clinical echocardiographic characteristics and cardiovascular outcome in patients with acute heart failure (HF) with versus without diabetes mellitus (DM). Demographic, clinical, laboratory, and echocardiographic data were collected in Olmsted County adults hospitalized for acute HF between 2005 and 2008. Analyses were performed for mortality and acute HF hospitalization outcomes stratified by diabetic status, systolic function, and diastolic function. There were 912 subjects who met inclusion criteria, and mean age was 79 (SD 13.1) years with 53% women. Prevalence of DM was 42% in the study population, and those with DM had worse diastolic function and increased mortality and HF rehospitalization. Among those with DM and acute HF, reduced left ventricular ejection fraction and worse diastolic function conferred increased HF rehospitalization (p = 0.010 and p = 0.022, respectively). In conclusion, DM is common in those hospitalized for acute HF and is associated with worse long-term clinical outcomes. The subgroup of DM with acute HF and left ventricular systolic dysfunction or diastolic dysfunction had worse HF rehospitalization outcomes.

Coenzyme Q10 in the Treatment of Heart Failure with Preserved Ejection Fraction: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common in elderly people and is increasing in prevalence. No specific treatment for this condition exists. Coenzyme Q10 (CoQ10) is an essential cofactor for energy production, with reduced levels being noted in HF. Previous studies have suggested a possible role for CoQ10 in the treatment of HF. This study examined the effect of CoQ10 supplementation on diastolic function in HFpEF patients. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial including patients aged > 55 years presenting with New York Heart Association class II-IV heart failure symptoms and left ventricular ejection fraction > 50%, with impaired diastolic function. Echocardiography and levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed at baseline and following 4 months of CoQ10 or placebo supplementation. RESULTS: A total of 39 patients were enrolled-19 in the CoQ10 group and 20 in the placebo group. Baseline clinical characteristics were similar between groups, while compliance was high and also similar between the CoQ10 and placebo groups. There was no significant effect of treatment on indices of diastolic function (difference in the lateral E/e' ratio: -0.86 ± 6.57 in the CoQ10 group, +0.18 ± 3.76 in the placebo group; p = 0.561) or on serum NT-proBNP levels (- 72 pg/mL vs. - 42 pg/mL; p = 0.195). CONCLUSIONS: In this pilot trial in elderly patients with HFpEF, treatment with CoQ10 did not significantly affect echocardiographic indices of diastolic function and serum NT-proBNP levels. TRIAL REGISTRATION: This trial was registered in the US National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier: NCT02779634).

In silico identification of potential calcium dynamics and sarcomere targets for recovering left ventricular function in rat heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex disease associated with multiple co-morbidities, where impaired cardiac mechanics are often the end effect. At the cellular level, cardiac mechanics can be pharmacologically manipulated by altering calcium signalling and the sarcomere. However, the link between cellular level modulations and whole organ pump function is incompletely understood. Our goal is to develop and use a multi-scale computational cardiac mechanics model of the obese ZSF1 HFpEF rat to identify important biomechanical mechanisms that underpin impaired cardiac function and to predict how whole-heart mechanical function can be recovered through altering cellular calcium dynamics and/or cellular contraction. The rat heart was modelled using a 3D biventricular biomechanics model. Biomechanics were described by 16 parameters, corresponding to intracellular calcium transient, sarcomere dynamics, cardiac tissue and hemodynamics properties. The model simulated left ventricular (LV) pressure-volume loops that were described by 14 scalar features. We trained a Gaussian process emulator to map the 16 input parameters to each of the 14 outputs. A global sensitivity analysis was performed, and identified calcium dynamics and thin and thick filament kinetics as key determinants of the organ scale pump function. We employed Bayesian history matching to build a model of the ZSF1 rat heart. Next, we recovered the LV function, described by ejection fraction, peak pressure, maximum rate of pressure rise and isovolumetric relaxation time constant. We found that by manipulating calcium, thin and thick filament properties we can recover 34%, 28% and 24% of the LV function in the ZSF1 rat heart, respectively, and 39% if we manipulate all of them together. We demonstrated how a combination of biophysically based models and their derived emulators can be used to identify potential pharmacological targets. We predicted that cardiac function can be best recovered in ZSF1 rats by desensitising the myofilament and reducing the affinity to intracellular calcium concentration and overall prolonging the sarcomere staying in the active force generating state.

Locomotor Muscle Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction.

[Figure: see text].

Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction: JACC State-of-the-Art Review.

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Annexin A1 attenuates cardiac diastolic dysfunction in mice with inflammatory arthritis.

Rheumatoid arthritis (RA) carries a twofold increased incidence of heart failure with preserved ejection fraction, accompanied by diastolic dysfunction, which can lead to death. The causes of diastolic dysfunction are unknown, and there are currently no well-characterized animal models for studying these mechanisms. Current medications for RA do not have marked beneficial cardio-protective effects. K/BxN F1 progeny and KRN control mice were analyzed over time for arthritis development, monitoring left ventricular diastolic and systolic function using echocardiography. Excised hearts were analyzed by flow cytometry, qPCR, and histology. In pharmacological experiments, K/BxN F1 mice were treated with human recombinant AnxA1 (hrAnxA1, 1 µg/mouse) or vehicle daily. K/BxN F1 mice exhibited fully developed arthritis with normal cardiac function at 4 wk; however, by week 8, all mice displayed left ventricular diastolic dysfunction with preserved ejection fraction. This dysfunction was associated with cardiac hypertrophy, myocardial inflammation and fibrosis, and inflammatory markers. Daily treatment of K/BxN F1 mice with hrAnxA1 from weeks 4 to 8 halted progression of the diastolic dysfunction. The treatment reduced cardiac transcripts of proinflammatory cytokines and profibrotic markers. At the cellular level, hrAnxA1 decreased activated T cells and increased MHC IIlow macrophage infiltration in K/BxN F1 hearts. Similar effects were obtained when hrAnxA1 was administered from week 8 to week 15. We describe an animal model of inflammatory arthritis that recapitulates the cardiomyopathy of RA. Treatment with hrAnxA1 after disease onset corrected the diastolic dysfunction through modulation of both fibroblast and inflammatory cell phenotype within the heart.

Effect of diabetes mellitus on the development of left ventricular contractile dysfunction in women with heart failure and preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with sex-specific pathophysiology. Estrogen deficiency is believed to be responsible for the development of HFpEF in women. However, estrogen deficiency does not seem to be completely responsible for the differences in HFpEF prevalence between sexes. While diabetes mellitus (DM) frequently coexists with HFpEF in women and is associated with worse outcomes, the changes in myocardial contractility among women with HFpEF and the DM phenotype is yet unknown. Therefore, we aimed to investigate sex-related differences in left ventricular (LV) contractility dysfunction in HFpEF comorbid with DM. METHODS: A total of 224 patients who underwent cardiac cine MRI were included in this study. Sex-specific differences in LV structure and function in the context of DM were determined. LV systolic strains (global longitudinal strain [GLS], circumferential strain [GCS] and radial strain [GRS]) were measured using cine MRI. The determinants of impaired myocardial strain for women and men were assessed. RESULTS: The prevalence of DM did not differ between sexes (p > 0.05). Despite a similar LV ejection fraction, women with DM demonstrated a greater LV mass index than women without DM (p = 0.023). The prevalence of LV geometry patterns by sex did not differ in the non-DM subgroup, but there was a trend toward a more abnormal LV geometry in women with DM (p = 0.072). The magnitudes of systolic strains were similar between sexes in the non-DM group (p > 0.05). Nevertheless, in the DM subgroup, there was significant impairment in women in systolic strains compared with men (p < 0.05). In the multivariable analysis, DM was associated with impaired systolic strains in women (GLS [ß = 0.26; p = 0.007], GCS [ß = 0.31; p < 0.001], and GRS [ß = -0.24; p = 0.016]), whereas obesity and coronary artery disease were associated with impaired systolic strains in men (p < 0.05). CONCLUSIONS: Women with DM demonstrated greater LV contractile dysfunction, which indicates that women with HFpEF comorbid with DM have a high-risk phenotype of cardiac failure that may require more aggressive and personalized medical treatment.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Prognostic relevance of elevated plasma osmolality on admission in acute decompensated heart failure with preserved ejection fraction: insights from PURSUIT-HFpEF registry.

BACKGROUND: Complicated pathophysiology makes it difficult to identify the prognosis of heart failure with preserved ejection fraction (HFpEF). While plasma osmolality has been reported to have prognostic importance, mainly in heart failure with reduced ejection fraction (HFrEF), its prognostic meaning for HFpEF has not been elucidated. METHODS: We prospectively studied 960 patients in PURSUIT-HFpEF, a multicenter observational study of acute decompensated HFpEF inpatients. We divided patients into three groups according to the quantile values of plasma osmolality on admission. During a follow-up averaging 366 days, we examined the primary composite endpoint of cardiac mortality or heart failure re-admission using Kaplan-Meier curve analysis and Cox proportional hazard testing. RESULTS: 216 (22.5%) patients reached the primary endpoint. Kaplan-Meier curve analysis revealed that the highest quantile of plasma osmolality on admission (higher than 300.3 mOsm/kg) was significantly associated with adverse outcomes (Log-rank P = 0.0095). Univariable analysis in the Cox proportional hazard model also revealed significantly higher rates of adverse outcomes in the higher plasma osmolality on admission (hazard ratio [HR] 7.29; 95% confidence interval [CI] 2.25-23.92, P = 0.0009). Multivariable analysis in the Cox proportional hazard model also showed that higher plasma osmolality on admission was significantly associated with adverse outcomes (HR 5.47; 95% CI 1.46-21.56, P = 0.0113) independently from other confounding factors such as age, gender, comorbid of atrial fibrillation, hypertension history, diabetes, anemia, malnutrition, E/e', and N-terminal pro-B-type natriuretic peptide elevation. CONCLUSIONS: Higher plasma osmolality on admission was prognostically important for acute decompensated HFpEF inpatients.

Clinical performance and exercise hemodynamics in patients with severe secondary tricuspid regurgitation and chronic atrial fibrillation.

OBJECTIVE: The study aimed to investigate the functional capacity and hemodynamics at rest and during exercise in patients with chronic atrial fibrillation and severe functional symptomatic tricuspid regurgitation (AF-FTR). BACKGROUND: Symptoms and clinical performance of severe AF-FTR mimic the population of patients with heart failure with preserved ejection fraction (HFpEF). Severe AF-FTR is known to be associated with an adverse prognosis whereas less is reported about the clinical performance including exercise capacity and hemodynamics in patients symptomatic AF-FTR. METHODS: Right heart catheterization (RHC) at rest and during exercise was conducted in a group of patients with stable chronic AF-TR and compared with a group of patients with HFpEF diagnosed with cardiac amyloid cardiomyopathy (CA). All patients had preserved ejection fraction and no significant left-sided disease. RESULTS: Patients with AF-FTR demonstrated a low exercise capacity that was comparable to CA patients (TR 4.9 ± 1.2 METS vs. CA 4. 7 ± 1.5 METS; P = 0.78) with an average peak maximal oxygen consumption of 15 mL/min/kg. Right atrium pressure increased significantly more in the AF-FTR patients as compared to CA patients at peak exercise (25 ± 8 vs 19 ± 9, p < 0.01) whereas PCWP increased significantly to a similar extent in both groups (31 ± 4 vs 31 ± 8 mmHg, p = 0.88). Cardiac output (CO) was significantly lower among AF-FTR at rest as compared to CA patients (3.6 ± 0.9 vs 4.4 ± 1.3 l/min; p < 0.05) whereas both groups demonstrated a poor but comparable CO reserve at peak exercise (7.3 ± 2.9 vs 7.9 ± 3.8 l/min, p = 0.59). CONCLUSIONS: AF-FTR contributes to the development of advanced heart failure symptoms and poor exercise capacity reflected in increased atrial filling pressures, reduced cardiac output at rest and during exercise sharing common features seen in HFpEF patients with other etiologies.

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.

Left atrial minimal volume: association with diastolic dysfunction and heart failure in patients in sinus rhythm or atrial fibrillation with preserved ejection fraction.

BACKGROUND: Evidence of diastolic dysfunction (DD) required for the diagnosis of heart failure with preserved ejection fraction (HFpEF) is elusive in atrial fibrillation (AF). Left ventricular (LV) and left atrial (LA) speckle-tracking echocardiography (STE) may provide rhythm independent indications of DD. We aimed to find common LV/LA myocardial mechanics parameters to demonstrate DD, using STE in patients with AF. METHODS: 176 echocardiographic assessments of patients were studied retrospectively by STE. 109 patients with history of AF were divided in three groups: sinus with normal diastolic function (n = 32, ND), sinus with DD (n = 35, DD) and patients with AF during echocardiography (n = 42). These assessments were compared to 67 normal controls. Demographic, clinical, echocardiographic and myocardial mechanic characteristics were obtained. RESULTS: The patients with DD in sinus rhythm and patients with AF were similar in age, mostly women, and had cardiovascular risk factors as well as higher dyspnea prevalence compared to either controls or patients with ND. In the AF group, LV ejection fraction (LVEF) (p = 0.008), global longitudinal strain and LA emptying were lower (p < 0.001), whereas LA volumes were larger (p < 0.001) compared to the other groups. In a multivariable analysis of patients in sinus rhythm, LA minimal volume indexed to body surface area (Vmin-I) was found to be the single significant factor associated with DD (AUC 83%). In all study patients, Vmin-I correlated with dyspnea (AUC 80%) and pulmonary hypertension (AUC 90%). CONCLUSIONS: Vmin-I may be used to identify DD and assist in the diagnosis of HFpEF in patients with AF.