Table 1.
Therapeutic options for the treatment of endothelial dysfunction in patients with heart failure.
| Study | Study Design | Key Findings |
|---|---|---|
| Exercise Training (ET) | ||
| Sandri M et al., 2016 [198] | RCT; 60 patients with chronic HF vs. 60 controls. |
ET vs. control group improved FMD, CD34/KDR+ EPCs, and migratory capacity of cultured mononuclear cells. |
| Chen J et al., 2021 [199] | RCT; 80 patients with chronic HF and ΕΤ. |
ET improved LVEF and LVFS. Additionally, ET had higher EPCs levels and proliferation ability and lower BNP levels and EPCs apoptosis rate. |
| Isaksen K et al., 2019 [132] | Controlled prospective trial; 30 patients with ischemic HF and ICD. |
ET vs. control group improved peak VO2 and endothelial function. |
| Kitzman DW et al., 2013 [202] | RCT; 63 patients with HFpEF. |
ET improved peak VO2 and quality of life but no endothelial function. |
| Angadi SS et al., 2015 [247] | RCT; 19 patients with HFpEF. |
High-intensity interval training improved peak VO2, LV diastolic dysfunction. No effect on endothelial function was demonstrated. |
| Statins | ||
| Oikonomou E et al., 2015 [205] | RCT; 26 patients with stable HF; evaluation of atorvastatin 10 mg/day vs. atorvastatin 40 mg/day for 4 weeks. |
40 mg/day Atorvastatin demonstrated higher EPCs and FMD values and decreased TNF-α levels in both compared groups. |
| Tousoulis D et al., 2011 [206] | RCT; 60 patients with systolic HF; administration of rosuvastatin 10 mg/day vs. allopurinol 300 mg/day or placebo. |
Rosuvastatin group had increased CD34/KDR+, CD34/CD133/KDR+ and EPCs levels. Additionally, improvement of endothelial was observed. |
| Erbs S et al., 2011 [207] | RCT; 42 patients with chronic HF randomized to 12 weeks of oral rosuvastatin (40 mg/d) or placebo. |
Rosuvastatin 40 mg/day increased VEGF levels, CD34+ stem cell count, number of CD34/KDR+ EPCs, EPC integrative capacity, and FMD. |
| Tousoulis D et al., 2005 [208] | RCT; 38 patients with HF: Group 1: atorvastatin 10 mg/day (n = 19), group 2: control (n = 19), duration of treatment: 4 weeks. |
Atorvastatin 10 mg/day improved forearm vasodilatory response to reactive hyperemia; decreased levels of IL-6, TNF-α, and sVCAM-1. |
| Tousoulis D et al., 2013 [209] | RCT; atorvastatin in 22 patients with ischemic HF. |
Atorvastatin 40 mg/day vs. 10 mg/day significantly improved FMD and AIx values. |
| Winzer EB et al., 2016 [248] | RCT; 18 patients with chronic HF; randomized to 12 weeks of rosuvastatin vs. placebo |
Rosuvastatin improved FMD and LDL cholesterol levels. Moreover, deterioration of FMD and LDL after cessation of therapy was detected. |
| Angiotensin-converting enzyme inhibitors (ACEi)/Angiotensin Receptor Inhibitors (ARBs) | ||
| Gibbs CR et al., 2001 [222] | Cross-sectional study; 120 patients with chronic HF and sinus rhythm; n = 20 on lisinopril vs. n = 20 on β blocker (carvedilol or bisoprolol) |
Initiation of beta-blocker therapy revealed no significant changes in hemorheological, endothelial function, and platelet indices. Moreover, initiation of ACEi decreased fibrinogen and vWF levels. |
| Hryniewicz K et al., 2005 [225] | RCT, 64 patients with chronic HF; randomization in placebo vs. 10 mg ramipril vs. 50 mg sildenafil vs. combination of ramipril/sildenafil. |
Ramipril vs. placebo increased FMD at 4 h. Moreover, Sildenafil vs. placebo increased FMD at 1, 2, and 4 h. Combination of sildenafil/ramipril vs. placebo increased FMD at 1, 2, and 4 h. |
| Safonova JI et al., 2022 [226] | Cross-sectional study; 40 patients with HF (n = 20 patients with HFpEF; n = 20 patients with HFmrEF); administration of 12-months perindopril. |
Perindopril increased in phase shift in both HFpEF and HFmrEF; increase in occlusion index in both HFpEF and HFmrEF; decreased E-selectin in both HFpEF and HFmrEF; ET-1 levels significantly decreased only in HFpEF |
| Ellis GR et al., 2002 [249] | RCT; 28 patients with HF on ACEi; randomization to candesartan vs. placebo |
Candesartan vs. placebo has no effects on brachial artery FMD, exercise capacity (peak VO2), and biomarkers of oxidative stress. |
| Nakamura M et al., 2002 [250] | RCT; 26 patients with congestive HF that randomized to losartan vs. placebo. |
Losartan group revealed increased forearm blood flow in response to intra-arterial infusion of acetylcholine. |
| Mineralocorticoid Receptor Antagonists (MRAs) | ||
| Farquharson et al., 2000 [232] | RCT; 10 patients with chronic HF on standard diuretic/ACEi therapy were randomized to 50 mg/day spironolactone vs. placebo for 1 month. |
Spironolactone improved forearm blood flow response to acetylcholine increased NO bioactivity, and inhibition of vascular angiotensin I/angiotensin II conversion. |
| Abiose AK et al., 2004 [233] | Cross-sectional; n = 20 patients with congestive HF; administration of spironolactone. |
Administration of spironolactone improved FMD at 4 and 8 weeks. |
| Macdonald JE et al., 2004 [251] | RCT; 43 patients with congestive HF under ACEi and beta blockers; administration of 12.5-50 mg/day spironolactone vs. placebo for 3 months. |
Administration of spironolactone increased acetylcholine-mediated vasodilatation and vascular ACE activity. Moreover, spironolactone decreased BNP and procollagen III N-terminal peptide. |
| Sodium-glucose cotransporter 2 (SGLT-2) inhibitors | ||
| Correale M et al., 2021 [252] |
Cross-sectional study; 22 patients with chronic HF and type 2 diabetes mellitus vs. n = 23 controls treated with other antidiabetic drugs |
SGLT2 i administration improved endothelial function and arterial stiffness. |
| Sezai A et al., 2019 [253] | Prospective cohort study; 35 Japanese patients with chronic HF; administration of canagliflozin for 12 months. |
Administration of canagliflozin decreased fat content at 12 months. Moreover, significant decrease in natriuretic peptides, improvement of renal function, FMD, E/e’ and oxidized LDL levels were reported after canagliflozin administration. |
| Sacubitril/Valsartan | ||
| Li BH et al., 2021 [245] | RCT; 80 patients with HFrEF; randomized to observation group (n = 40, sacubitril/valsartan plus conventional treatment) vs. control group (n = 40, perindopril plus conventional treatment) for 12 weeks. |
Sacubitril valsartan improves endothelial function while increasing cardiac function in HFrEF patients. |
| Bunsawat K et al., 2021 [254] | Prospective cohort study; 11 patients with HFrEF under optimal treatment; administration of sacubitril-valsartan for 3 months. |
Administration of sacubitril/valsartan improved FMD at 1 month and at 2-3 months. Moreover, decreased levels of TNF-α and IL-18 were reported. |
| Du H et al., 2022 [255] | RCT; 60 patients with chronic HF and hypertension; randomly divided into observation group (n = 30, sacubitril/valsartan) and control group (n = 30, valsartan) for 6 months. |
Sacubitril/valsartan subjects reported improvement in endothelium-dependent vasodilation, serum NO, and decreased ET-1 levels. |
| Nathaniel S et al., 2022 [246] | Case-control study; 20 HFrEF patients (n = 10 on sacubitril/valsartan vs. n = 10 on conventional treatment with ACEi/ARBs) for 12 weeks. |
Sacubitril/valsartan decreased PWV and improved FMD. |
| Amore L et al., 2022 [244] | Prospective cohort study; 15 patients with dilated cardiomyopathy and reduced LVEF; administration of sacubitril/valsartan for 6 months. |
Administration of sacubitril/valsartan shows an increase in reactive hyperemia index and AIx six months after first administration. |
| Endothelin receptor antagonists (ERAs) | ||
| Karavolias GK et al., 2010 [256] | Cross-sectional study; 16 patients with moderate-severe idiopathic PAH under conventional treatment; administration of bosentan (62.5 mg twice daily for 1 month followed by 125 mg twice daily for 11 months). |
Bosentan therapy modifies endothelial cell activation by down-regulating the levels of ICAM-1 at 2 months. |
| Iannone F et al., 2008 [257] | Cross-sectional study; 35 patients with systemic sclerosis (n = 10 with isolated PAH) vs. n = 25 healthy subjects; administration of bosentan in patients with isolated PAH. |
Administration of bosentan for 12 months down-regulated endothelial activation and reduced ICAM-1, VCAM-1, P-selectin, PECAM-1, CD3 LFA-1 T, and CD3-L-selectin T-cell levels. |
| Sfikakis PP et al., 2007 [258] | RCT; Cross-sectional study, 12 patients with systemic sclerosis/PAH who received bosentan for 4 weeks vs. n = 12 patients without bosentan. |
Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes. |
ADMA: asymmetric dimethylarginine; ACEi: Angiotensin-converting enzyme inhibitor; Alx: Augmentation index; ARBs: Angiotensin Receptor Inhibitors; BNP: Brain natriuretic peptide; EID: endothelial independent dilation; EPCs: endothelial progenitor cells; ERAs: Endothelin receptor antagonists; ET: Exercise training; ET-1: Endothelin-1; FMD: flow-mediated dilatation; HFrEF: heart failure with reduced ejection fraction; HFmrEF: heart failure with mildly reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; ICD: Implantable cardioverter defibrillator; IL: interleukin; IVUS: Intravascular ultrasound; LFA-1: Lymphocyte function-associated antigen-1; LVEF: left ventricular ejection fraction; LVFS: left ventricular short-axis shortening rate; LVEDD: left ventricular end-diastolic diameter; LVESD: left ventricular end-systolic diameter; MRA: Mineralocorticoid Receptor Antagonists; MMP: matrix metalloproteinase; MPO: myeloperoxidase; NT-proBNP: N-terminal pro-brain natriuretic peptide; oxLDL: oxidized low-density lipoprotein; PAH: Pulmonary arterial hypertension; PAP: Pulmonary artery pressure; PECAM-1: platelet/endothelial cell adhesion molecule; PerOx: total lipid peroxides; PVR: pulmonary vascular resistance; PWV: Pulse wave velocity; RCT: Randomized controlled trial; RHI: reactive hyperemia index; RH-PAT; reactive hyperemia-peripheral arterial tonometry; SGLT2 i: Sodium-glucose-cotransporter-type-2 inhibitors; sVCAM-1: soluble vascular cell adhesion molecule; sICAM-1: soluble intercellular adhesion molecule; SDF-1: stromal-derived factor 1; SMD: Standardized mean difference; TNF-α: tumor necrosis factor alpha; VEGF: vascular endothelial growth factor; vWF: von Willebrand factor.