Abstract
PurposeAvailable animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented.MethodsMyocardial infarction (MI) was induced by occlusion of left anterior descending coronary artery in 17 male pigs (34 ± 4 kg). Two weeks later, ADHF was induced in the survived animals (n = 15) by occlusion of the circumflex coronary artery, associated with acute volume overload and increases in arterial blood pressure by vasoconstrictor infusion. After onset of ADHF, animals received 48-h iv infusion of either serelaxin (n = 9) or placebo (n = 6). The pathophysiology and progression of ADHF were described by combining evaluation of hemodynamics, echocardiography, bioimpedance, blood gasses, circulating biomarkers, and histology.ResultsDuring ADHF, animals showed reduced left ventricle (LV) ejection fraction < 30%, increased thoracic fluid content > 35%, pulmonary edema, and high pulmonary capillary wedge pressure ~ 30 mmHg (p < 0.01 vs. baseline). Other ADHF-induced alterations in hemodynamics, i.e., increased central venous and pulmonary arterial pressures; respiratory gas exchanges, i.e., respiratory acidosis with low arterial PO2 and high PCO2; and LV dysfunction, i.e., increased LV end-diastolic/systolic volumes, were observed (p < 0.01 vs. baseline). Representative increases in circulating cardiac biomarkers, i.e., troponin T, natriuretic peptide, and bio-adrenomedullin, occurred (p < 0.01 vs. baseline). Finally, elevated renal and liver biomarkers were observed 48 h after onset of ADHF. Mortality was ~ 50%. Serelaxin showed beneficial effects on congestion, but none on mortality.ConclusionThis new model, resulting from a combination of chronic and acute MI, and volume and pressure overload, was able to reproduce all the typical clinical signs occurring during ADHF in a consistent and reproducible manner.
Highlights
Acute heart failure (AHF) is characterized by a gradual or rapid onset of new or worsening signs and symptoms of heart failure (HF), usually requiring hospitalization for urgent therapy
Animals were considered in acute decompensated heart failure (ADHF) when all the following three criteria were met: (1) a sustained left ventricular ejection fraction (LVEF) < 30%, (2) a 3-fold increase in PWCP, and (3) an increase of thoracic fluid content (TFC) of more than 25% from the baseline value
Criteria for ADHF were achieved in all animals, with a reduction in LVEF < 30% and increases in TFC > 25% from baseline and in pulmonary capillary wedge pressure (PCWP) to values of 28 ± 2 mmHg (p < 0.01 vs. baseline, Table 1 and Fig. 3)
Summary
Acute heart failure (AHF) is characterized by a gradual or rapid onset of new or worsening signs and symptoms of heart failure (HF), usually requiring hospitalization for urgent therapy. AHF is the most common cause for hospital admission in patients over 65 years, with approximately 1 million hospitalizations per year in the USA and Europe, and a high burden of costs, i.e., over $60 billion/year [1]. Despite improvements in the management of HF patients, the prognosis after hospitalization for AHF remains bleak, with rates of death or recurrent hospitalization at 6 months approaching 50% [2]. Lung congestion leading to dyspnea is the main reason for hospitalization in patients with acute decompensated heart failure (ADHF). Among patients discharged from the hospital for ADHF, only 32.9% are alive and have not been rehospitalized after 1 year [3]. Widespread efforts to develop new drug treatments, as well as to develop robust preclinically animal models to test therapeutic interventions, are highly motivated [2,3,4,5]
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