Is reversal of endothelial dysfunction still an attractive target in modern cardiology?

Table 2 Selected studies examining pharmacological reversal of endothelial dysfunction

Ref.	Drug	Cohort	Design	Results
Mancini et al[94]	Quinapril	105 normotensive patients with coronary artery disease	Randomised double-blind, placebo controlled	Quinapril improved endothelial function compared to placebo as measured by coronary artery diameter response to acetylcholine
Higashi et al[96]	Various ACE inhibitors, beta-blockers, calcium channel blockers and diuretics	296 hypertensive patients	Multi-centre cohort study	ACE inhibitors significantly improved endothelial dependent vasodilatation compared to other drug classes as measured by forearm blood flow
Wassmann et al[97]	Candesartan, felodipine	47 patients with high cholesterol	Randomised double-blind, placebo controlled	Candesartan improved forearm blood flow compared to felodipine or placebo
Ghiadoni et al[98]	Nifedipine, amlodipine Perindopril, telmisartan, atenolol, nebivolol	168 patients with hypertension	Randomized, single-blind, parallel-group	Only perindopril improved FMD (although perindopril, telmisartan, nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity)
Tzemos et al[99]	Valsartan, amlodipine	25 hypertensive patients	Randomised double-blind, crossover	Valsartan improved forearm blood flow
Takagi et al[100]	Telmisartan	Mixed; 398 patients	Meta-analysis of 7 studies	Statistically significant increase in FMD by 48.7%
Farquaharson et al[101]	Spironolactone	10 patients with NYHA class I-II heart failure	Randomised, double-blind placebo-controlled crossover study	Spironolactone improved forearm blood flow compared to placebo
MacDonald et al[103]	Spironolactone	43 patients with NYHA class I-II heart failure	Randomised, double-blind crossover study	Spironolactone improved forearm blood flow compared to placebo
Abiose et al[104]	Spironolactone	20 patients with NYHA class III-IV congestive heart failure	Cohort study	Spironolactone improved FMD at 4 wk with a sustained improvement at 8 wk
Tzemos et al[107]	Nebivolol, atenolol	12 hypertensive patients	Randomised, double-blind crossover study	Only nebivolol was able to improve endothelial dependent vasodilation
Pasini et al[108]	Nebivolol, atenolol	40 hypertensive patients with 40 controls	Randomised double-blind parallel group	FMD improved only in the group treated with nebivolol
Matsuda et al[109]	Carvedilol	29 patients with coronary artery disease	Randomised, placebo controlled	Carvedilol significantly improved FMD after 4 mo treatment
Agewall et al[116]	Atorvastatin	20 healthy smokers, 20 healthy non-smokers	Open label placebo controlled randomised cross-over	Smokers had a lower baseline FMD. Atorvastatin improved FMD in smokers but had no effect in non-smokers
Ostad et al[117]	Atorvastatin, ezetimibe	58 patients with coronary artery disease	Double-blind, randomised, parallel group	High-dose atorvastatin improved FMD significantly more than low dose atorvastatin + ezetimibe independently of improvement in LDL cholesterol
Gounari et al[118]	Rosuvastatin, ezetimibe	Patients with heart failure	Double-blind, placebo controlled, cross-over trial	Rosuvastatin caused a significant improvement of FMD compared to ezetimibe and independent of LDL cholesterol and baseline brachial artery diameter
Pitocco et al[121]	Metformin	42 type 1 diabetics without overt cardiovascular disease	Randomised double-blind, placebo controlled	Significant improvement in FMD by 1.32% compared to placebo
Lamendola et al[122]	Ranolazine	30 type 2 (non-insulin dependent) diabetics without overt cardiovascular disease	Randomised double-blind, placebo controlled	Significant improvement in FMD compared to placebo after 2 wk of ranolazine therapy
Kao et al[123]	Allopurinol	67 patients with CKD stage 3 and LV hypertrophy	Randomized, double-blind, parallel-group	Significant improvement in FMD compared to placebo after 9 mo of allopurinol therapy

FMD: Flow-mediated dilation.