Cardiovascular diseases are major contributors to global deaths and disability-adjusted life years, with hypertension a significant risk factor for all causes of death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions, such as vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of obtaining measurements of endothelial function, the clinical techniques for its determination, the mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunction. Since vascular oxidative stress and inflammation are major determinants of endothelial function, we have also addressed current antioxidant and anti-inflammatory therapies. In the light of recent data that dispute the prognostic value of endothelial function in healthy human cohorts, we also discuss alternative diagnostic parameters such as vascular stiffness index and intima/media thickness ratio. We also suggest that assessing vascular function, including that of smooth muscle and even perivascular adipose tissue, may be an appropriate parameter for clinical investigations.

Linked Articles
This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13517

Targeting vascular (endothelial) dysfunction

Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets?

The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00540.2011

Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities

BACKGROUNDHigh-speed rotational atherectomy uses a diamond-coated, elliptical burr to abrade occlusive atherosclerosis, especially noncompliant calcified plaque.METHODS AND RESULTSIntravascular ultrasound (IVUS) was used to analyze 28 patients after atherectomy. Arteries treated and imaged were left main (three), left anterior descending (12), left circumflex (five), right coronary (seven), and saphenous vein graft (one). Twenty patients had adjunct balloon angioplasty. Twenty-two (79%) target lesions were calcified; the intimal arc of calcium was 160 +/- 126 degrees (range, 0-360 degrees). After atherectomy, the intima-lumen interface was unusually distinct and circular. The lumen was larger than the largest burr used for both stand-alone (1.19 +/- 0.19-fold the largest burr size) and adjunct balloon procedures (1.30 +/- 0.15-fold the largest burr). Three-dimensional reconstruction of the ultrasound images showed a smooth lumen, especially in calcified plaque. Deviations from cylindrical geometry occurre...

Intravascular ultrasound evaluation of the effect of rotational atherectomy in obstructive atherosclerotic coronary artery disease.

Nitric oxide (NO) is an important regulator of vascular and myocardial function. Cardiac ischemia/reperfusion injury is reduced in mice overexpressing endothelial NO synthase (eNOS) suggesting cardioprotection by eNOS. Novel pharmacological substances, so called eNOS enhancers, upregulate eNOS expression and thereby increase NO production. We tested the effects of the eNOS enhancer AVE 9488 on cardiac ischemia/reperfusion injury in vivo in mice. After treatment with the eNOS enhancer AVE 9488 (30 mg/kg/day) or placebo for one week mice underwent 30 min of coronary artery ligation and 24 h of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in mice treated with the eNOS enhancer when compared to placebo treated mice (infarct/area at risk 65.4 ± 4.1 vs. 36.9 ± 4.0%, placebo vs. eNOS enhancer, P = 0.0002). The protective effect was blunted in eNOS knockout mice treated with the eNOS enhancer (infarct/area at risk 64.1 ± 6.2%, eNOS knockout + eNOS enhancer vs. WT + eNOS enhancer, P = ns). Reactive oxygen species were significantly reduced in mice treated with the eNOS enhancer as indicated by significantly lower malondialdehyde–thiobarbituric acid levels (placebo vs. eNOS enhancer, 3.2 ± 0.5 vs. 0.8 ± 0.07 μmol/l, P = 0.0003). Thus pharmacological interventions addressed to increase eNOS-derived NO production constitute a promising therapeutic approach to prevent myocardial ischemia/reperfusion injury.

The eNOS enhancer AVE 9488: a novel cardioprotectant against ischemia reperfusion injury


 
 
 The approval of new therapies for treating transthyretin (TTR) cardiac amyloidosis has led to significant interest in identifying patients at high risk for this disease. Investigators have identified a correlation between severe degenerative aortic stenosis (AS) and TTR cardiac amyloidosis in older patients, with several studies finding up to 20% of patients who undergo transcatheter aortic valve replacement (TAVR) having TTR cardiac amyloidosis. These initial TAVR studies were conducted when TAVR was performed almost exclusively in high surgical risk populations. Therefore, the true incidence of TTR cardiac amyloidosis in an all-comers with severe degenerative AS referred for TAVR is unknown.
 
 
 
 To identify the true burden of TTR cardiac amyloidosis in a contemporary population of severe degenerative AS undergoing TAVR screening.
 
 
 
 All patients ≥70 years with severe native valve degenerative AS seen in a multidisciplinary valve clinic were referred for technetium-99m pyrophosphate cardiac scintigraphy (PYP scan) for evaluation of cardiac amyloidosis. Diagnosis was made via combination of planar grade and heart to contralateral lung ratio, confirmed on single positron emission computed tomography/computed tomography (SPECT/CT). Patients with a positive PYP scan were referred to a heart failure clinic where they underwent testing for AL amyloidosis.
 
 
 
 Over a 10 month period, 247 patients seen in valve clinic underwent a PYP scan. Of this cohort, 203 patients ultimately underwent TAVR, 15 surgical aortic valve replacement, and 2 balloon valvuloplasty with 27 patients having not yet undergone a procedure. The positivity rate was 4% (10/247) with 1 patient having an equivocal result. The patients with a positive PYP scan had higher rate of low-flow low-gradient (LFLG) AS (64% vs 29%, p=0.006) and classical LFLG AS (27% vs 8%, p=0.02). Echocardiographic measures associated with a positive PYP scan include a lower global longitudinal strain (−10.0% vs −16.1%, p=0.008), lower average e' (4.5 vs 6.5, p=0.003), and an increased E/A ratio (1.8 vs 1.1, p=0.018).
 
 
 
 The incidence of TTR amyloidosis in a contemporary, severe AS population ≥70 years undergoing TAVR screening appears much lower than previously described in the literature. Echocardiographic traits may be able to predict which patients with severe AS should undergo evaluation for TTR cardiac amyloidosis.
 
 
 
 Type of funding sources: None.


/pdf/incidence-and-predictors-of-transthyretin-cardiac-1hh8g8o6.pdf

Incidence and predictors of transthyretin cardiac amyloidosis in patients with degenerative aortic stenosis

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The eNOS enhancer AVE 9488: a novel cardioprotectant against ischemia reperfusion injury

Incidence and predictors of transthyretin cardiac amyloidosis in patients with degenerative aortic stenosis