Interleukin-1 blockade in recently decompensated systolic heart failure: study design of the recently decompensated heart failure anakinra response trial (RED-HART)

Heart Failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, and poor exercise capacity due to impaired cardiac function. The incidence of HF is increasing and represents the leading cause of hospitalization in the United States among patients > 65 years of age. Neurohormonal blockade has proven to reduce morbidity and mortality; however the persistent toll of HF demonstrates the urgent need to continue to develop novel drugs that target other pathophysiological paradigms. The presence of inflammation in cardiovascular disease has been well-established and interleukin-1 (IL-1), the prototypical proinflammatory agent, has been shown in preclinical animal models to induce cardiac dysfunction. The current study will investigate the role of IL-1 as an inflammatory mediator of HF progression and investigate whether IL-1 blockade with anakinra, recombinant human IL-1 receptor antagonist, improves aerobic exercise performance in patients with recently decompensated systolic HF. This study will be composed of 3 treatment arms (20 patients each): 1) anakinra 100mg daily for 12 weeks; 2) anakinra 100mg daily for 2 weeks followed by placebo for 10 weeks; or 3) placebo for 12 weeks. All patients will be followed for at least 24 weeks. The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) measured by Cardiopulmonary Exercise Testing (CPX) after 2 weeks of anakinra treatment. Secondary endpoints will include interval changes in 1) CPX variables at 4, 12 and 24 weeks; 2) echocardiographic measures of cardiac dimension/function; 3) quality of life assessments; 4) inflammatory biomarkers; and 5) clinical outcome including days alive outside of the hospital and survival free of re-hospitalization for HF. The RED-HART study will be the first study to address the potential benefits of IL-1 blockade on aerobic exercise performance in patients with recently decompensated HF

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (AT(II)) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the AT(II) (0.2 mg·kg(−1)·day(−1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. AT(II) infusion had no effects on systemic arterial blood pressure. AT(II) induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose AT(II) recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF

Transapical and Transfemoral Aortic Valve Implantation. Impact and General Considerations of both Approaches

Background: Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic option in inoperable or high surgical risk patients with severe symptomatic aortic stenosis. The transapical approach is an alternative access for patients with contraindications for the transfemoral access. Objective: The aim of this study was to evaluate the feasibility and reproducibility of transapical TAVI and compare the short and mid-term outcome with that of transfemoral TAVI. Methods: A cohort of 80 patients undergoing transapical (n=24) and transfemoral (n=56) TAVI was retrospectively evaluated. Procedure-related complications as defined by VARC-2 criteria, and short-term and mid-term mortality were analyzed and compared in both groups. Results: Patients in the transapical group were older (83.6 ± 5 vs. 80.0 ± 8.3; p = 0.04) and had greater prevalence of coronary artery disease (75 vs. 44%; p = 0.04) and peripheral vascular disease (37% vs. 16%; p = 0.01). Patients in the transapical group had lower fluoroscopy time (14.9 minutes ± 5.8 vs. 22.9 minutes ± 8.7; p = 0.001) and presented a non-significant trend toward greater requirement of dialysis after the procedure (12.5% vs. 1.8%, p = 0.13). Hospital stay was longer in the transapical group (13.6 ± 23 days vs. 7-2 ± 6.9 days, p = 0.05). Mortality at 30 days and one year was greater in the transapical group (20.8% vs. 5.4%; p = 0.03 and 25% vs. 8.9%; p = 0.04), respectively.  Conclusions: In our experience, transapical TAVI is a feasible and reproducible procedure for patients with severe symptomatic aortic stenosis unsuitable for transfemoral approach. Transapical access was associated with increased risk of mortality at 30 days, in agreement with several publications.Introducción: El implante valvular aórtico percutáneo (TAVI) ha surgido como una alternativa terapéutica en pacientes con estenosis aórtica grave sintomática inoperables o de elevado riesgo quirúrgico. El acceso transapical surge como alternativa para aquellos pacientes con contraindicación de implante valvular aórtico percutáneo transfemoral. Objetivo: Valorar la factibilidad y la reproducibilidad del implante valvular aórtico percutáneo transapical en nuestro centro y comparar la evolución a corto y mediano plazo con los pacientes sometidos a implante valvular aórtico percutáneo transfeoral. Material y métodos: Se evaluó una cohorte retrospectiva de 80 pacientes tratados con implante valvular aórtico percutáneo transapical (n = 24) y transfemoral (n = 56) en nuestro centro. Se compararon las complicaciones relacionadas con el procedimiento según las definiciones VARC-2, y se analizó la mortalidad a corto y mediano plazo entre ambos grupos. Resultados: Los pacientes del grupo transapical eran más añosos (83,6 ± 5 versus 80,0 ± 8,3; p = 0,04); presentaron mayor prevalencia de coronariopatía (el 75% versus el 44%; p = 0,04) y mayor prevalencia de vasculopatía periférica (el 37% versus el 16%; p = 0,01). El grupo transapical tuvo menor exposición a rayos X, (tiempo de fluoroscopia de 14,9 minutos ± 5,8 versus 22,9 minutos ± 8,7; p = 0,001); y una mayor tendencia a requerir diálisis luego del procedimiento (el 12,5% versus 1,8%, p = 0,13). El grupo transapical permaneció más tiempo internado (13,6 ± 23 días versus 7,2 ± 6,9 días, p = 0,05). La mortalidad a 30 días fue mayor en el grupo transapical (el 20,8% versus el 5,4%; p = 0,03) y al año (el 25% versus el 8,9%; p = 0,04). Conclusiones: En nuestra experiencia, el implante valvular aórtico percutáneo transapical es factible y puede ser realizado como un procedimiento reproducible para pacientes no aptos para el implante valvular aórtico percutáneo transfemoral. El acceso transapical se asoció con mayor mortalidad durante el seguimiento, particularmente en el período posoperatorio a 30 días, lo que coincide con varios reportes publicados