Pascal McKeown

Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities

Abstract—Antioxidant vitamins C and E have protective properties in genetic hypertension associated with enhanced oxidative stress. This study investigated whether vitamins C and/or E modulate vascular function by regulating enzymatic activities of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had impaired relaxant responses to acetylcholine but not to sodium nitroprusside, despite an ≈2-fold increase in eNOS activity and NO release. The levels of superoxide anion (O2−), a potent NO scavenger, and NAD(P)H oxidase activity were also 2-fold higher in SHR aortas. Mechanical but not pharmacological inactivation of endothelium (by rubbing and 100 &mgr;mol/L L-NAME, respectively) significantly abrogated O2− in both strains. Treatments of SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and apocynin, significantly diminished O2− production. The incubation of SHR aortas with different concentrations of vitamin C (10 to 100 &mgr;mol/L) and specifically with high concentrations of vitamin E (100 &mgr;mol/L) improved endothelial function, reduced superoxide production as well as NAD(P)H oxidase activity, and increased eNOS activity and NO generation in SHR aortas to the levels observed in vitamin C- and E-treated WKY aortas. Our results reveal endothelial NAD(P)H oxidase as the major source of vascular O2− in SHR and also show that vitamins C and E are critical in normalizing genetic endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities.

The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation

OBJECTIVE Enhanced oxidative stress is involved in mediating the endothelial dysfunction associated with hypertension. The aim of this study was to investigate the relative contributions of pro-oxidant and anti-oxidant enzymes to the pathogenesis of endothelial dysfunction in genetic hypertension. METHODS Dilator responses to endothelium-dependent and endothelium-independent agents such as acetylcholine (ACh) and sodium nitroprusside were measured in the thoracic aortas of 28-week-old spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar Kyoto rats (WKY). The activity and expression (mRNA and protein levels) of endothelial nitric oxide synthase (eNOS), p22-phox, a membrane-bound component of NAD(P)H oxidase, and antioxidant enzymes, namely, superoxide dismutases (CuZn- and Mn-SOD), catalase and glutathione peroxidase (GPx), were also investigated in aortic rings. RESULTS Relaxant responses to ACh were attenuated in phenylephrine-precontracted SHR aortic rings, despite a 2-fold increase in eNOS expression and activity. Although the activity and/or expression of SODs, NAD(P)H oxidase (p22-phox) and GPx were elevated in SHR aorta, catalase activity and expression remained unchanged compared to WKY. Pretreatment of SHR aortic rings with the inhibitor of xanthine oxidase, allopurinol, and the inhibitor of cyclooxygenase, indomethacin, significantly potentiated ACh-induced relaxation. Pretreatment of SHR rings with catalase and Tiron, a superoxide anion (O(2)(-)) scavenger, increased the relaxant responses to the levels observed in WKY rings whereas pyrogallol, a O(2)(-)-generator, abolished relaxant responses to ACh. CONCLUSION These data demonstrate that dysregulation of several enzymes, resulting in oxidative stress, contributes to the pathogenesis of endothelial dysfunction in SHR and indicate that the antioxidant enzyme catalase is of particular importance in the reversal of this defect.

Paced ventricular electrogram fractionation predicts sudden cardiac death in hypertrophic cardiomyopathy.

AIMS Paced electrogram fractionation analysis (PEFA) has been assessed for the prediction of sudden cardiac death (SCD) in a large-scale, prospective study of patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS We determined the positive predictive value (PPV) of PEFA in relation to other risk factors for SCD and outcomes in 179 patients with HCM and no prior history of cardiac arrest. Patients were followed over a mean 4.3 years (range: 1.1-6.3 years). Thirteen patients had SCD-equivalent events: four of these patients died suddenly, three were resuscitated from ventricular fibrillation (VF), and six had implantable cardioverter-defibrillator (ICD) discharges in response to VF. PEFA identified nine of these patients and another 14 non-VF patients yielding a censored PPV of between 0.19 and 0.59 that was greater than the PPV that was the formal stopping point of the trial (0.18). Eighty per cent of patients were followed for 4 years or more. The PPV for the identification of SCD in this group was 0.38 (0.17-0.59). The use of two or more conventional markers to predict SCD identified five patients with SCD-equivalent events in the 4-year follow-up group and 42 other patients without events yielding a PPV of 0.106 (confidence limits 0.02-0.15). CONCLUSION PEFA identifies HCM patients at risk of SCD with greater accuracy than non-invasive techniques and may have an important role in determining indications for ICD prescription.

The Role of Micronutrients in Heart Failure

Heart failure is a common condition in the Western world, particularly among elderly persons and with an ever-aging population, the incidence is expected to increase. Diet in the setting of heart failure is important--patients with this condition are advised to consume a low-salt diet and monitor their weight closely. Nutritional status of patients with heart failure also is important--those with poor nutritional status tend to have a poor long-term prognosis. A growing body of evidence suggests an association between heart failure and micronutrient status. Reversible heart failure has been described as a consequence of severe thiamine and selenium deficiency. However, contemporary studies suggest that a more subtle relationship may exist between micronutrients and heart failure. This article reviews the existing literature linking heart failure and micronutrients, examining studies that investigated micronutrient intake, micronutrient status, and the effect of micronutrient supplementation in patients with heart failure, and focusing particularly on vitamin A, vitamin C, vitamin E, thiamine, other B vitamins, vitamin D, selenium, zinc, and copper.

Nutritional intake and oxidative stress in chronic heart failure

BACKGROUND AND AIMS Patients with chronic heart failure (CHF) are known to be at risk of malnutrition, and cardiac cachexia is an adverse prognostic indicator. The aim of this study was to determine the dietary adequacy of CHF patients compared with Dietary Reference Values, to compare the nutritional intake and status of CHF patients to a healthy comparison group, and finally to determine whether nutritional intake and status depended on New York Heart Association (NYHA) functional class. METHODS AND RESULTS Patients with CHF (n = 39) and a comparison group of 27 healthy participants, who did not have CHF, were asked to complete a four-day food diary, and energy and nutrient intakes were calculated. F(2α)-isoprostanes were measured in urine as an indicator of oxidative stress and antioxidants were measured in serum or plasma. Overall 73% of the CHF patients were consuming less than recommended energy intakes, and more than 50% of these patients were also consuming less than recommended vitamin D, selenium and zinc intakes. Nutrient intake (energy, vitamin B6, D, E, iron, folate and riboflavin) was lower in CHF patients than in the comparison group, with vitamin B6 and folate intake and antioxidant status decreasing, and isoprostane status increasing as NYHA functional class increased. CONCLUSION The majority of CHF patients do not meet dietary reference values for energy and a range of nutrients, and nutrient intake is lower in CHF patients than in healthy individuals. Dietary inadequacy tends to be increased in those with more severe disease.

Voriconazole-induced pseudoporphyria.

Pseudoporphyria is a bullous photosensitivity, the commonest aetiology being secondary to various ingested medications. Voriconazole is a relatively new second‐generation triazole antifungal agent. There have only been two reports of pseudoporphyria secondary to voriconazole. We report the third case of this phenomenon occurring in a lady being treated for disseminated candidal infection.

Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes

Whilst the decision regarding defibrillator implantation in a patient with a familial sudden cardiac death syndrome is likely to be most significant for any particular individual, the clinical decision-making process itself is complex and requires interpretation and extrapolation of information from a number of different sources. This document provides recommendations for adult patients with the congenital Long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although these specific conditions differ in terms of clinical features and prognosis, it is possible and logical to take an approach to determining a threshold for implantable cardioveter-defibrillator implantation that is common to all of the familial sudden cardiac death syndromes based on estimates of absolute risk of sudden death.

Antioxidant vitamins C and E ameliorate hyperglycaemia‐induced oxidative stress in coronary endothelial cells

Objective:  Vitamins C and E have protective features in many disease states associated with enhanced oxidative stress. The aim of this study was to investigate whether vitamin(s) C and/or E modulate hyperglycaemia‐induced oxidative stress by regulating enzymatic activities of prooxidant, i.e. NAD(P)H oxidase and/or antioxidant enzymes, namely endothelial nitric oxide synthase (eNOS), superoxide dismutase, catalase and glutathione peroxidase, using coronary microvascular endothelial cells (CMEC).

Adoption and maintenance of a Mediterranean diet in patients with coronary heart disease from a Northern European population: a pilot randomised trial of different methods of delivering Mediterranean diet advice.

BACKGROUND A Mediterranean diet has been shown to protect against coronary heart disease (CHD). Adherence to a Mediterranean diet can be assessed using a Mediterranean diet score. The primary aim of this pilot study was to examine whether CHD patients in a Northern European population would adopt and maintain a Mediterranean diet, with a secondary aim of comparing the effectiveness of different methodologies aimed at improving compliance. METHODS Sixty-one patients with a diagnosis of CHD were randomised to one of three groups: either to receive conventional dietetic advice for CHD or advice to implement a Mediterranean-style diet using either behavioural counselling or nutritional counselling. Patients received a follow-up assessment at 6 months (adoption) and a subset of patients was followed up at 12 months (maintenance). The primary outcome measure was the between-group difference in the mean change in Mediterranean diet score (MDS). RESULTS The change in MDS was not significantly different between groups. However, all three groups reported a significant within-group increase in MDS (P < 0.01) at 6 and 12 months follow-up. CONCLUSIONS All three groups made dietary changes towards a Mediterranean diet, but behavioural counselling did not have significant additional benefit over nutritional counselling in initiating and maintaining dietary change, and neither method offering specific Mediterranean diet advice had any significant benefit in terms of improvement in MDS over conventional dietetic practice.