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Sudden cardiac death (SCD) is a common late complication in patients with tetralogy of Fallot (ToF). Reduced baroreflex sensitivity (BRS) is an independent predictor of SCD and BRS reduction was reported in ToF. Relationship between BRS and carotid artery distensibility (DC) in healthy subjects was reported by us earlier. We also found that DC was reduced in ToF patients. In the present study we tested the hypothesis that reduced BRS is related to increased carotid artery stiffness. We studied 36 ToF patients (21±11 years) and 60 age-matched healthy control subjects. Intravenous phenylephrine-induced (BRSphe) and spontaneous (BRSseq) BRS indices were derived. DC calculation was based on echo wall-tracking and tonometry. BRS indices were reduced in patients compared with controls (BRSphe 16.8±10.2 vs. 27.3±9.2ms/mmHg; BRSseq 9.3±9.2 vs. 18.3±7.8ms/mmHg). DC was also lower in patients (5.1±1.8 vs. 6.3±2.610(-3)/mmHg). BRS correlated with DC across patients and controls (BRSphe r=0.75 vs. r=0.74; BRSseq r=0.44 vs. r=0.38). Multiple regression analysis indicated that BRS indices are determined independently by DC in ToF patients. We showed that reduced DC may contribute to impaired baroreflex function in ToF patients and could in part explain the elevated risk for SCD postoperatively. Therefore it would be an important future investigation to test carotid artery stiffness and analyze its predictive value for cardiac mortality in ToF. Preventive actions to impede carotid artery stiffening should receive more attention in the clinical management of ToF patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In various diseased states reduced cardiac vagal activity is accompanied by impaired endothelial function. Evidence from animal studies indicates interaction between the two systems, but such data from human studies is limited. The aim of this study was to test the hypothesis that cardiac vagal activity and endothelial function are related in healthy individuals. 46 young males were studied. From 10 minute long ECG recordings mean RR-interval and time and frequency domain vagal heart rate variability indices (RMSSD; pNN50 and HF, respectively) were determined. Heart rate variability indices were used to define cardiac vagal activity. Endothelial function was assessed by measuring brachial artery flow mediated dilation. Hyperemic, diastolic shear rate was used to normalize flow mediated dilation. All three vagal heart rate variability indices correlated significantly and positively with flow mediated dilation across subjects, with r values within the range of 0.43-0.52, p<0.01 for all relations. After adjusting for potential confounders, vagal heart rate variability indices remained significantly associated with normalized flow mediated dilation. RR-interval was related to most heart rate variability indices, but was not related to flow mediated dilation. Our data demonstrate that vagal heart rate variability indices are related to flow mediated dilation across healthy male subjects. The results cannot serve as evidence of a causal relationship, but are of interest and render for further investigation into underlying mechanisms., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Carotid artery stiffness, an important determinant of arterial baroreflex sensitivity, varies considerably in healthy individuals, the source of which variability is not known. Tonic relaxant influence of the endothelium on vascular smooth muscle, reducing stiffness of the vessel wall, has been established in muscular conduit arteries. It is not known to what extent stiffness of the elastic carotid artery is under endothelial control., Subjects and Methods: Seventy-one healthy male volunteers were studied. Endothelial function was assessed by brachial artery flow mediated dilatation (FMD) normalized by diastolic shear rate (SRd). Carotid artery elastic parameters were determined by echo wall-tracking and tonometry. Systemic arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV)., Results: In univariate analysis carotid artery elastic parameters were related to BMI and systolic blood pressure, but were not related to any of endothelial function parameters. As expected, PWV was related inversely to nFMD. No relation was found between vascular stiffness parameters and endothelium-independent dilation (EID)., Conclusion: Carotid artery elasticity in health is not related to conduit artery FMD, suggesting that endothelial influence on baroreceptor activity is not exerted through changes in barosensory wall elasticity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Previous studies raised the possibility that nitric oxide synthase is present in heart mitochondria (mtNOS) and the existence of such an enzyme became generally accepted. However, original experimental evidence is rather scarce and positive identification of the enzyme is lacking. We aimed to detect an NOS protein in human and mouse heart mitochondria and to measure the level of NO released from the organelles. Western blotting with 7 different anti-NOS antibodies failed to detect a NOS-like protein in mitochondria. Immunoprecipitation or substrate-affinity purification of the samples concentrated NOS in control preparations but not in mitochondria. Release of NO from live respiring human mitochondria was below 2 ppb after 45 min of incubation. In a bioassay system, mitochondrial suspension failed to cause vasodilation of human mammary artery segments. These results indicate that mitochondria do not produce physiologically relevant quantities of NO in the heart and are unlikely to have any physiological importance as NO donors, nor do they contain a recognizable mtNOS enzyme.

Arterial baroreflex sensitivity (BRS) is markedly reduced in middle-aged patients with end-stage renal disease (ESRD), due to the combined effects of aging, arterial stiffening, and autonomic neuropathy. Much less is known about the effects of ESRD on arterial baroreflex in juvenile patients. Therefore, we investigated baroreflex function and its relation to carotid artery elasticity and heart rate variability in children and young adults with ESRD. We studied 42 subjects (9-30 years): 14 patients on maintenance hemodialysis (HD), 14 renal transplant recipients (RT), and 14 healthy control subjects (C). Baroreflex function was determined by pharmacological (BRS) and spontaneous (sequence and spectral indices) techniques. Carotid artery elasticity was characterized by stiffness index beta. Heart rate variability was assessed using time and frequency domain measures. Data are expressed as mean+/-s.d. BRS was markedly reduced in HD as compared to C (10.0+/-4.2 vs 25.7+/-5.9 ms/mm Hg); spontaneous indices were reduced to similar extent. Carotid artery stiffness was approximately 50% higher in HD than in C and was inversely related to BRS. Heart rate variability was also compromised in HD, and was directly related to spontaneous indices. No significant differences existed in any of these variables between RT and C. Decreased baroreflex function in juvenile HD is partly due to loss of carotid artery elasticity and partly due to impaired heart rate variability. Renal transplantation may partly prevent impairment or improve compromised baroreflex function in young patients with ESRD.

It is more than 10 years now that mitochondria are suspected to be sources of nitric oxide (NO). This hypothesis is intriguing since NO has multiple targets within the organelle and it is even suggested that mitochondria are the primary targets of NO in the cell. Most remarkably, nanomolar concentrations of NO can inhibit mitochondrial respiration, so even a small amount of NO in the mitochondrial matrix may regulate ATP synthesis. Therefore, the idea that mitochondria themselves are capable of NO production is an important concept in several physiological and pathological mechanisms. However, this field of research generates surprisingly few original papers and the published studies contain conflicting results. The reliability of the results is frequently questioned since they are seldom reproduced by independent investigators. Until 2003, all papers published in this field showed affirmative results but since then several studies directly challenged the existence of a mitochondrial nitric oxide synthase. The present review aims to summarize the most recent developments in mitochondrial NO production, highlights a few unsolved questions, and proposes new directions for future work in this research area.

Introduction: Several fluorescent probes were designed for the measurement of nitric oxide (NO), however, questions arose regarding their specificity and sensitivity in biological samples. In the present study we tested the reaction of a novel rhodamine-based chromophore diaminorhodamine-4M (DAR-4M) with NO and other reactive nitrogen and oxygen species., Methods: We performed fluorometry in 96-well plates in a cell-free buffer with similar ion concentrations as the cytoplasm. Dose-response curves were generated using various NO donors and reactive nitrogen and oxygen species. The effects were compared between the red-fluorescent DAR-4M and its green-fluorescent counterpart 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM)., Results: DAR-4M had a markedly higher fluorescence yield to NO donors than DAF-FM, while both probes had a comparable threshold of sensitivity (in the range of 0.1 mM nitroprusside). Both dyes reacted with various NO donors in a dose-dependent manner, while superoxide, hydrogen peroxide, peroxynitrite, or nitroxyl failed to change the fluorescence intensity of the probes. DAR-4M was potentiated in the presence of peroxynitrite to react with low levels of NO donors in a similar manner to DAF-FM., Discussion: We conclude that DAR-4M is a suitable red-fluorescent probe for the qualitative assessment of reactive nitrogen species production, but not specific for NO. Quantitative comparisons among samples is inappropriate since the fluorescent yield is affected by the presence of other oxidants in the sample.

Oxidant-mediated activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. The aim of the current study was to investigate whether activation of PARP contributes to the development of endothelial dysfunction in the apolipoprotein E (ApoE) deficient mice. We tested whether PARP inhibition prevents the development of endothelial dysfunction and whether it restores function in vessels with established endothelial dysfunction. ApoE deficient mice were kept on high-fat diet for 12 weeks with and without INO-1001 treatment. Chronic treatment with the PARP inhibitor INO-100 reduced the degree of the endothelial dysfunction (the ability of the vessel to relax to acetylcholine) in the thoracic aortae of ApoE deficient mice. In addition, in vitro incubation of vessels from ApoE deficient mice with established endothelial dysfunction with the PARP inhibitor acutely improved the ability of the rings to relax to acetylcholine. We conclude that the early atherosclerotic functional alterations that develop in the endothelium of the ApoE deficient mice are, at least in part, reversible, and are dependent on the activation of the nuclear enzyme PARP in the endothelial cells.

In this study we tested the hypothesis that dietary vitamin E supplementation can improve carotid artery elasticity and cardio-vagal baroreflex gain in young, healthy individuals. A total of 20 subjects were studied in a double-blind, placebo-controlled, randomized study. Subjects in the active treatment group received 700 IU/day vitamin E for 1 month. Each subject was studied three times: before, during and 1 month after treatment. Plasma vitamin E levels were determined using high-performance liquid chromatography. Carotid artery diameter was measured by ultrasound and radial artery pressure by tonometry. Baroreflex function was assessed by time and frequency domain spontaneous indices. Plasma vitamin E levels increased by 123%, which was associated with a 20% increase in carotid artery compliance and a 30-60% increase in baroreflex indices. All these changes regressed 1 month after cessation of vitamin E supplementation. Significant correlations were observed across conditions (control, treatment and recovery), among plasma vitamin E concentrations, carotid artery compliance and distensibility values and two of the baroreflex gain indices in the treatment group. Our results demonstrate that vitamin E supplementation can increase carotid artery compliance and baroreflex gain in young, apparently healthy adults.

We compared aortic arch (AA) and carotid sinus (CS) distensibility, and determined the relationship between baroreflex sensitivity (BRS) and distensibility coefficients of AA and CS (DCAA and DCCS, respectively). In 47 healthy 19-71-year-old subjects, AA and CS end-diastolic diameter (D) and pulsatile distension (delta D) was measured with ultrasound and arterial pressure by sphygmomanometer and Finapres. DC was calculated as 2delta D/(D x delta P), where delta P is the pulse pressure. BRS was determined by the sequence method. Data are given as mean +/- S.D.; significance was set at p < 0.05. DCAA and DCCS were linearly related across subjects (r = 0.80, p < 0.001). No difference between DCAA and DCCS (3.8 +/- 1.4 x 10(-3) and 4.2 + 2.2 x 10(-3) mm Hg(-1), respectively) was found for all subjects (paired t-test). However, at ages < 35 years, DCCS exceeded DCAA, whereas this relation was reversed at ages > 35 years. Age accounted for 53% of variability in DCAA and 73% of variability in DCCS. BRS was related to DC (linear regression), with the BRS-DCAA relation being steeper and closer (r = 0.73, p < 0.001) than the BRS-DCCS relation (r = 0.54, p < 0.05). It is suggested that aortic baroreceptors may have a dominant role in heart rate control.

A generally increased vagal nervous activity was suggested to exist in bronchial asthma; however, this contention has never been fully tested. Before studying vagal activity in asthma, we raised the question if there existed any relation between vagal outflows to different target organs in the physiologic state. The specific aim of this study was to determine the relation between the resting level of bronchial and cardiac vagal activity in healthy volunteers. Bronchial and cardiac vagal tone were measured in 12 subjects as the change of airway resistance (Raw) and heart period (HP) in response to complete cholinergic blockade. It was found that after intravenous atropine administration, Raw was reduced from 1.30 +/- 0.41 cm H2O/L/s to 0.51 +/- 0.22 cm H2O/L/s and HP was reduced from 789 +/- 84 ms to 506 +/- 41 ms. All the values are given as mean +/- SD. Both the bronchial and cardiac responses exhibited considerable interindividual variability, but there was no significant correlation between them (R = 0.22, p = 0.50). It was concluded that under resting conditions, vagal control of bronchial tone and HP were not related in healthy human subjects.