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The use of direct acting vasodilators (the combination of hydralazine and isosorbide dinitrate -Hy+ISDN-) in heart failure with reduced ejection fraction (HFrEF) is supported by evidence, but rarely used.However, treatment with Hy+ISDN is guideline-recommended for HFrEF patients who cannot receive either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers due to intolerance or contraindication, and in self-identified African-American HFrEF patients who are symptomatic despite optimal neurohumoral therapy.The Hy+ISDN combination has arterial and venous vasodilating properties. It can decrease preload and afterload, decrease left ventricular end-diastolic diameter and the volume of mitral regurgitation, reduce left atrial and left ventricular wall tension, decrease pulmonary artery pressure and pulmonary arterial wedge pressure, increase stroke volume, and improve left ventricular ejection fraction, as well as induce left ventricular reverse remodelling. Furthermore, Hy+ISDN combination has antioxidant property, it affects endothelial dysfunction beneficially and improves NO bioavailability. Because of these benefits, this combination can improve the signs and symptoms of heart failure, exercise capacity and quality of life, and, most importantly, reduce morbidity and mortality in well-defined subgroups of HFrEF patients.Accordingly, this therapeutic option can in many cases play an essential role in the treatment of HFrEF.