Pulmonary Artery Diameter (PAD) and the Pulmonary Artery to Aorta Ratio (PAD/AAD) as Assessed by Non-contrast Cardiac CT: The Association with Left Ventricular (LV) Remodeling and the LV Function

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

Download Full-text

Abstract 3295: De-induction of the Maladaptive Fetal Gene Program During Chronic Monotherapy with Metoprolol Succinate is Retained Following Withdrawal of Therapy in Dogs with Chronic Heart Failure

Circulation ◽

10.1161/circ.116.suppl_16.ii_742-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Rasha Bazari ◽

Sharad Rastogi ◽

Valerio Zaca ◽

Sidney Goldstein ◽

Hani N Sabbah

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Mrna Expression ◽

Natriuretic Peptide ◽

Left Ventricular ◽

Lv Function ◽

Metoprolol Succinate ◽

Myosin Heavy Chain Isoform ◽

Chronic Therapy ◽

Lv Remodeling

Background: Chronic therapy with extended release metoprolol succinate (MET), a selective β1 adrenergic receptor blocker, improves left ventricular (LV) function and attenuates global LV remodeling in dogs with chronic heart failure (HF). We previously showed that chronic therapy with β-blockade results in de-induction of the fetal gene program (FGP) in LV myocardium of dogs with HF. In this study, we tested the hypothesis that in dogs with HF withdrawal of chronic MET does not lead to re-induction of FGP. Methods: Studies were performed in 17 intracoronary microembolization-induced HF dogs randomized to 3 months oral therapy with MET (100 mg, once daily, n=11) or no therapy at all (Controls, n=6). In dogs randomized to MET, 6 were sacrificed after 3 months of therapy and in the remaining 5, MET was withdrawn after 3 months of therapy and dogs were observed for 6 weeks after withdrawal of MET (MET-W) and then sacrificed. LV tissue was also obtained from 6 normal (NL) dogs for comparison. mRNA expression of the FGP genes namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), sarcoplasmic reticulum calcium ATPase (CAA), cardiac β-1 adren-ergic receptor (AR) and α-myosin heavy chain isoform (α-MHC) was measured using reverse transcriptase polymerase chain reaction (RT-PCR) and bands were quantified in densitometric units (du). Results: In Controls, mRNA expression of ANP and BNP increased and expression of CAA, β 1-AR and α-MHC decreased. Treatment with MET decreased expression of ANP and BNP and increased expression of CAA, β 1-AR and α-MHC. Except for α-MHC, the improvement in FGP seen during MET treatment was preserved in MET-W dogs. Conclusions: Withdrawal of MET is associated with sustained de-induction of the FGP in LV myocardium of dogs with HF. This observation supports the concept that chronic β-blockade therapy in HF confers lasting reversal of LV remodeling and molecular recovery of the failing myocardium.

Download Full-text

Abstract 14952: Hemodynamic Comparison of Left Ventricular Function in Pressure Overload- versus Volume Overload-Induced Heart Failure Models by Invasive Pressure-Volume Analysis

Circulation ◽

10.1161/circ.142.suppl_3.14952 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Mihály Ruppert ◽

Christian Karime ◽

Alex A Sayour ◽

Attila Oláh ◽

Dávid Nagy ◽

...

Keyword(s):

Heart Failure ◽

Systolic Function ◽

Pressure Overload ◽

Volume Overload ◽

Detailed Comparison ◽

Left Ventricular ◽

Lv Function ◽

Arterial Elastance ◽

Lv Remodeling ◽

Av Shunt

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p<0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p<0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p>0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p<0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.

Download Full-text

Benefits of long-term β-blockade in experimental chronic aortic regurgitation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01286.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. H1888-H1895 ◽

Cited By ~ 40

Author(s):

Eric Plante ◽

Dominic Lachance ◽

Serge Champetier ◽

Marie-Claude Drolet ◽

Élise Roussel ◽

...

Keyword(s):

Adrenergic Receptor ◽

Diastolic Pressure ◽

Left Ventricular ◽

Prolonged Treatment ◽

Adrenergic System ◽

Lv Function ◽

Adrenergic Blockade ◽

Long Term Effects ◽

Lv Remodeling

The objective of this study was to assess the long-term effects of β-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a β-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg·kg−1·day−1) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals ( P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). β-Adrenergic receptor ratio (β1/β2) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the β-adrenergic receptor ratio.

Download Full-text

Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00044.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. E243-E253 ◽

Cited By ~ 70

Author(s):

Vernon W. Dolinsky ◽

Kyle J. Rogan ◽

Miranda M. Sung ◽

Beshay N. Zordoky ◽

Mark J. Haykowsky ◽

...

Keyword(s):

Oxidative Stress ◽

Aerobic Exercise ◽

Exercise Performance ◽

Cardiac Injury ◽

Left Ventricular ◽

Aerobic Exercise Training ◽

Lv Function ◽

Endoplasmic Reticulum Calcium ◽

Lv Remodeling

Because doxorubicin (DOX)-containing chemotherapy causes left ventricular (LV) dysfunction and remodeling that can progress to heart failure, strategies to alleviate DOX cardiotoxicity are necessary to improve health outcomes of patients surviving cancer. Although clinical evidence suggests that aerobic exercise training (ET) can prevent cardiotoxicity in patients undergoing DOX chemotherapy, the physiological mechanisms involved have not been extensively studied, nor is it known whether compounds [such as resveratrol (RESV)] have similar beneficial effects. With the use of a murine model of chronic DOX exposure, this study compared the efficacy of modest ET to RESV treatment on exercise performance, LV remodeling, and oxidative stress resistance. Mice were divided into four groups that received saline, DOX (8 mg/kg ip, one time per week), DOX + RESV (4 g/kg diet, ad libitum), and DOX + ET (45 min of treadmill exercise, 5 days/wk) for 8 wk. LV function and morphology were evaluated by in vivo echocardiography. DOX caused adverse LV remodeling that was partially attenuated by modest ET and completely prevented by RESV. These effects were paralleled by improvements in exercise performance. The cardioprotective properties of ET and RESV were associated with reduced levels of atrial natriuretic peptide and the lipid peroxidation by-product, 4-hydroxy-2-nonenal. In addition, ET and RESV increased the expression of cardiac sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a, superoxide dismutase, mitochondrial electron transport chain complexes, and mitofusin-1 and -2 in mice administered DOX. Compared with modest ET, RESV more effectively prevented DOX-induced LV remodeling and was associated with the reduction of DOX-induced oxidative stress. Our findings have important implications for protecting patients against DOX-associated cardiac injury.

Download Full-text

Abstract 18200: Intracoronary Delivery of Bioabsorbable Alginate Matrix (IK-5001) Ameliorates Adverse Post-infarction Left Ventricular Remodeling and Improves Left Ventricular Function in a Porcine Model of Reperfused Myocardial Infarction

Circulation ◽

10.1161/circ.132.suppl_3.18200 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Carlos G Santos-Gallego ◽

Belén Picatoste ◽

Ida U Njerve ◽

Kiyotake Ishikawa ◽

Jaime Aguero ◽

...

Keyword(s):

Porcine Model ◽

Ventricular Remodeling ◽

Interstitial Fibrosis ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Lv Function ◽

Contractile Reserve ◽

Intracoronary Injection ◽

Lv Remodeling

Background: Adverse cardiac remodeling after MI is associated with excessive degradation of the extracellular matrix (ECM). IK-5001 is a low viscosity injectable solution that provides the polysaccharide alginate. After intracoronary injection into the MI area it undergoes phase transition forming a hydrogel which can support the ECM. We hypothesized that administration of alginate post-MI would provide a temporary scaffold and attenuate adverse LV remodeling. Methods: Acute MI was induced in 16 pigs by balloon occlusion of the proximal LAD for 2 hours. Animals randomly received intracoronary alginate or saline 4 days post-MI. LV function and remodeling were evaluated with cardiac MRI, 3D-echo and pressure-volume loops at 1 and 2 months post-MI. Histology and Western blot analysis were performed after 2 months. Results: Both groups had similar LVEF and infarct size 4 days post-MI. Coronary angiography immediately after alginate injection showed no impairment in coronary flow. However, 2 months post-MI, alginate-treated pigs exhibited reduced LV remodeling compared with controls demonstrated by reduced LV end-systolic volume, LV mass and sphericity (Table). Alginate-treated pigs had less cardiomyocyte hypertrophy and decreased interstitial fibrosis. Consistent with this, chronic activation of Akt and ERK was reduced. Alginate pigs also showed lower plasma levels of BNP and aldosterone. Interestingly, after 2 months, alginate pigs showed better systolic LV function: higher LVEF, better contractile reserve with dobutamine, and higher dP/dt. Conclusions: Intracoronary administration of alginate ameliorates adverse post-MI LV remodeling at the anatomical, histological and molecular level, and mitigates neurohormonal activation in a porcine model of MI. Alginate also improves systolic LV function. Intracoronary injection of alginate represents an exciting novel treatment option to reduce post-MI remodeling that merits assessment in clinical studies.

Download Full-text

Left ventricular dyssynchrony and post-systolic shortening in young bodybuilders using anabolic-androgenic steroids

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00136.2021 ◽

2021 ◽

Author(s):

Antoine Grandperrin ◽

Iris Schuster ◽

Thomas Rupp ◽

Omar IZEM ◽

Philippe Obert ◽

...

Keyword(s):

Left Ventricular ◽

Left Ventricular Dyssynchrony ◽

Anabolic Androgenic Steroids ◽

Lv Function ◽

Ventricular Dyssynchrony ◽

Lv Dyssynchrony ◽

2D Strain ◽

Lv Remodeling ◽

Androgenic Steroids ◽

Longitudinal Strains

Background: Left ventricular (LV) remodeling, characterized by increased LV hypertrophy and depressed function, is observed in strength-trained athletes who use anabolic-androgenic steroids (AAS). Previous studies reported an increase in cardiac fibrosis in these athletes, which could promote intraventricular dyssynchrony. In this context, this study evaluated LV dyssynchrony in strength-trained athletes using AA; hypothesizing that the use of AAS leads to an increase in LV dyssynchrony with an increase in post-systolic shortening. Methods: Forty-four participants (aged 20-40 years) were divided into three age-matched groups: strength-trained athletes using AAS (users, n=14) and those who were not (non-users, n=15), and healthy sedentary men (controls, n=15),. After completing a survey, each participant was assessed with 2D-strain echocardiography. Left ventricular dyssynchrony was quantified using the standard deviation of the time to peak for longitudinal strains (SD), the longitudinal strain delay index (LSDI) and the segmental post-systolic index (PSI). Results: Users exhibited a greater LV mass index and higher systolic and diastolic functions than both controls and non-users. The decrease in LV strains in users was predominantly observed at the interventricular segments. The SD, LSDI and PSI, calculated on the basal inferoseptal, basal anteroseptal and basal inferolateral segments, were higher in users. Conclusion: The results strongly support that the specific LV remodeling observed in young AAS users was associated with an increase in LV dyssynchrony. The correlations with ejection fraction suggested that wasted energy, due to post-systolic shortenings, contributed in part to the decrease in LV function in strength-trained athletes using AAS.

Download Full-text

Abstract 14915: Incidence, Predictors and Clinical Impact of Left Ventricular Functional Recovery Following Coronary Artery Bypass Grafting in Patients With Ischemic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.14915 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Masaro Nakae ◽

Satoshi Kainuma ◽

Koichi Toda ◽

Shigeru Miyagawa ◽

Daisuke Yoshioka ◽

...

Keyword(s):

Ischemic Cardiomyopathy ◽

Artery Bypass ◽

Left Ventricular ◽

Lv Function ◽

Term Survival ◽

Function Recovery ◽

Lv Remodeling ◽

Relationship Of

Introduction: CABG is considered the standard treatment for patients with ischemic cardiomyopathy (ICM). However, it remains unknown who would achieve postoperative LV function recovery after CABG. Furthermore, the relationship of postoperative LV function recovery with long-term outcomes remains unclear. Hypothesis: In patients with ICM who undergo CABG, postoperative LV function recovery, which would be influenced by degree of LV remodeling at baseline, is associated with improved outcomes. Methods: This multicenter retrospective study comprised 490 cases with LVEF of ≤40% who underwent CABG between 1993 and 2015. Clinical follow-up was completed in 467 cases (95%), with a mean follow-up of 65±46 months (range, 0-266). A total of postoperative echocardiographic assessments were carried with an average number of 3.7±2.4. LV function recovery was defined as LVEF ≥35% at more than one exam. Association of LV function recovery with mortality after adjustments for clinically relevant covariates was estimated using Cox proportional hazard model. Pre- and intraoperative associates of LV function recovery were identified using logistic regression model. Results: During follow-up, there were 203 mortalities (41%) and overall 10-year survival was 45%. LV function recovery was found in 368 cases (75%), while not in 122 (25%). Overall 10-year survival was significantly higher in patients who achieved LV function recovery as compared with those who did not achieve it (52% vs. 23%). Multivariate analysis identified LV function recovery was independently associated with decreased overall mortality (adjusted HR 0.40, p<0.0001). Preoperative LVDs (adjusted OR 0.92, p<0.0001), eGFR (adjusted OR 1.12, p=0.016) and revascularization using bilateral internal thoracic arteries (BITA) (adjusted OR 2.81, p=0.018) are the independent predictors of LV function recovery. Conclusions: Among patients with ICM who underwent CABG, 75% achieved substantial postoperative LV function recovery, in association with better long-term survival, as compared with the remaining 25% of patients who did not achieve it. Preoperative less LV remodeling and preserved renal function as well as revascularization with use of BITA might be associated with LV function recovery.

Download Full-text

Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00671.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. H1997-H2005 ◽

Cited By ~ 19

Author(s):

Ali Pourdjabbar ◽

Thomas G. Parker ◽

Quang Trinh Nguyen ◽

Jean-Francois Desjardins ◽

Nathalie Lapointe ◽

...

Keyword(s):

Gene Expression ◽

Ventricular Arrhythmias ◽

Angiotensin Receptor Blockers ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Lv Function ◽

High Dose ◽

Postmyocardial Infarction ◽

Lv Remodeling ◽

Cardiac Hemodynamics

Angiotensin receptor blockers (ARBs) reduce adverse left ventricular (LV) remodeling and improve LV function and survival when started postmyocardial infarction (MI). ARBs also reduce ventricular arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the ARB losartan improves the outcome when started pre-MI and continued peri- and post-MI. Male Wistar rats ( n = 502) were treated for 7 days pre-MI with losartan at a high dose (30 mg·kg−1·day−1), progressively increasing dose (3 mg·kg−1·day−1 increased to 10 mg·kg−1·day−1 10 days and 30 mg·kg−1·day−1 20 days post-MI), or no treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24 h post-MI. Echocardiography was done 30 days post-MI, and LV remodeling, cardiac hemodynamics, and fetal gene expression were assessed 38 days post-MI. High-dose losartan reduced 24-h post-MI survival compared with the progressive dose and control (21.9% vs. 36.6% and 38.1%, P = 0.033 and P = 0.009, respectively). This was associated with greater hypotension in the high dose and no change in ventricular arrhythmias in all groups. In 24-h post-MI survivors, the progressive dose group had reduced mortality from 24 h to 38 days (8.5% vs. 28.6% for control vs. 38.9% for high dose, P = 0.032 and P = 0.01, respectively). Survivors of both losartan groups demonstrated improved LV remodeling, cardiac hemodynamics, preserved GLUT-4, and reduced cardiac fetal gene expression. Pretreatment with ARBs does not reduce 24-h post-MI ventricular arrhythmias or survival, and high doses increase mortality by causing excessive hypotension. In 24-h post-MI survivors, progressively increasing doses of losartan have multiple beneficial effects, including improved survival.

Download Full-text

Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00485.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. H1513-H1523 ◽

Cited By ~ 27

Author(s):

Monique C. de Waard ◽

Jolanda van der Velden ◽

Nicky M. Boontje ◽

Dick H. W. Dekkers ◽

Rien van Haperen ◽

...

Keyword(s):

Myocardial Infarction ◽

Exercise Training ◽

Left Ventricular ◽

Lv Function ◽

Enos Expression ◽

Beneficial Effects ◽

Protein Levels ◽

Enos Uncoupling ◽

Lv Remodeling ◽

Exercise Induced

It has been reported that exercise after myocardial infarction (MI) attenuates left ventricular (LV) pump dysfunction by normalization of myofilament function. This benefit could be due to an exercise-induced upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. Consequently, we first tested the hypothesis that the effects of exercise after MI can be mimicked by elevated eNOS expression using transgenic mice with overexpression of human eNOS (eNOSTg). Both exercise and eNOSTg attenuated LV remodeling and dysfunction after MI in mice and improved cardiomyocyte maximal force development (Fmax). However, only exercise training restored myofilament Ca2+-sensitivity and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a protein levels and improved the first derivative of LV pressure at 30 mmHg. Conversely, only eNOSTg improved survival. In view of these partly complementary actions, we subsequently tested the hypothesis that combining exercise and eNOSTg would provide additional protection against LV remodeling and dysfunction after MI. Unexpectedly, the combination of exercise and eNOSTg abolished the beneficial effects on LV remodeling and dysfunction of either treatment alone. The latter was likely due to perturbations in Ca2+ homeostasis, as myofilament Fmax actually increased despite marked reductions in the phosphorylation status of several myofilament proteins, whereas the exercise-induced increases in SERCA2a protein levels were lost in eNOSTg mice. Antioxidant treatment with N-acetylcysteine or supplementation of tetrahydrobiopterin and l-arginine prevented these detrimental effects on LV function while partly restoring the phosphorylation status of myofilament proteins and further enhancing myofilament Fmax. In conclusion, the combination of exercise and elevated eNOS expression abolished the cardioprotective effects of either treatment alone after MI, which appeared to be, at least in part, the result of increased oxidative stress secondary to eNOS “uncoupling.”

Download Full-text