Recurrence of ventricular fibrillation in out-of-hospital cardiac arrest: Clinical evidence and underlying ionic mechanisms.

Defibrillation remains the optimal therapy for terminating ventricular fibrillation (VF) in out-of-hospital cardiac arrest (OHCA) patients, with reported shock success rates of ∼90%. A key persistent challenge, however, is the high rate of VF recurrence (∼50-80%) seen during post-shock cardiopulmonary resuscitation (CPR). Studies have shown that the incidence and time spent in recurrent VF are negatively associated with neurologically-intact survival. Recurrent VF also results in the administration of extra shocks at escalating energy levels, which can cause cardiac dysfunction. Unfortunately, the mechanisms underlying recurrent VF remain poorly understood. In particular, the role of chest-compressions (CC) administered during CPR in mediating recurrent VF remains controversial. In this review, we first summarize the available clinical evidence for refibrillation occurring during CPR in OHCA patients, including the postulated contribution of CC and non-CC related pathways. Next, we examine experimental studies highlighting how CC can re-induce VF via direct mechano-electric feedback. We postulate the ionic mechanisms involved by comparison with similar phenomena seen in commotio cordis. Subsequently, the hypothesized contribution of partial cardiac reperfusion (either as a result of CC or CC independent organized rhythm) in re-initiating VF in a globally ischaemic heart is examined. An overview of the proposed ionic mechanisms contributing to VF recurrence in OHCA during CPR from a cellular level to the whole heart is outlined. Possible therapeutic implications of the proposed mechanistic theories for VF recurrence in OHCA are briefly discussed.

The influence of scenario-based training and real-time audiovisual feedback on out-of-hospital cardiopulmonary resuscitation quality and survival from out-of-hospital cardiac arrest.

STUDY OBJECTIVE: We assess whether an initiative to optimize out-of-hospital provider cardiopulmonary resuscitation (CPR) quality is associated with improved CPR quality and increased survival from out-of-hospital cardiac arrest. METHODS: This was a before-after study of consecutive adult out-of-hospital cardiac arrest. Data were obtained from out-of-hospital forms and defibrillators. Phase 1 included 18 months with real-time audiovisual feedback disabled (October 2008 to March 2010). Phase 2 included 16 months (May 2010 to September 2011) after scenario-based training of 373 professional rescuers and real-time audiovisual feedback enabled. The effect of interventions on survival to hospital discharge was assessed with multivariable logistic regression. Multiple imputation of missing data was used to analyze the effect of interventions on CPR quality. RESULTS: Analysis included 484 out-of-hospital cardiac arrest patients (phase 1 232; phase 2 252). Median age was 68 years (interquartile range 56-79); 66.5% were men. CPR quality measures improved significantly from phase 1 to phase 2: Mean chest compression rate decreased from 128 to 106 chest compressions per minute (difference -23 chest compressions; 95% confidence interval [CI] -26 to -19 chest compressions); mean chest compression depth increased from 1.78 to 2.15 inches (difference 0.38 inches; 95% CI 0.28 to 0.47 inches); median chest compression fraction increased from 66.2% to 83.7% (difference 17.6%; 95% CI 15.0% to 20.1%); median preshock pause decreased from 26.9 to 15.5 seconds (difference -11.4 seconds; 95% CI -15.7 to -7.2 seconds), and mean ventilation rate decreased from 11.7 to 9.5/minute (difference -2.2/minute; 95% CI -3.9 to -0.5/minute). All-rhythms survival increased from phase 1 to phase 2 (20/231, 8.7% versus 35/252, 13.9%; difference 5.2%; 95% CI -0.4% to 10.8%), with an adjusted odds ratio of 2.72 (95% CI 1.15 to 6.41), controlling for initial rhythm, witnessed arrest, age, minimally interrupted cardiac resuscitation protocol compliance, and provision of therapeutic hypothermia. Witnessed arrests/shockable rhythms survival was 26.3% (15/57) for phase 1 and 55.6% (20/36) for phase 2 (difference 29.2%; 95% CI 9.4% to 49.1%). CONCLUSION: Implementation of resuscitation training combined with real-time audiovisual feedback was independently associated with improved CPR quality, an increase in survival, and favorable functional outcomes after out-of-hospital cardiac arrest.

A new defibrillator mode to reduce chest compression interruptions for health care professionals and lay rescuers: a pilot study in manikins.

BACKGROUND: Chest compression interruptions are detrimental during the resuscitation of cardiac arrest patients, especially immediately prior to shock delivery. OBJECTIVE: To evaluate the effect of use of a new defibrillator technology, which filters compression-induced artifact and provides reliable rhythm analysis with automatic defibrillator charging during chest compressions, on preshock chest compression interruption. METHODS: Thirty subjects (20 basic life support [BLS]; 10 advanced life support [ALS]) worked in pairs to perform two randomly ordered simulated cardiac resuscitations with the defibrillator operating in either standard mode (ALS = manual; BLS = automated external defibrillator [AED]) or the new Analysis and Charging during CPR (AC-CPR) mode. During each resuscitation simulation, rescuers switched roles as chest compressor and defibrillator operator every two segments of CPR (one segment = 2 minutes of chest compressions, rhythm analysis, and shock delivery, if appropriate), for eight total segments. The participants rested ≥30 minutes between trials and received brief AC-CPR training (BLS = 30 seconds; ALS = 5 minutes). Heart rate and perceived exertion were measured with pulse oximetry and the Borg scale, respectively. RESULTS: Mean (± standard deviation) preshock chest compression pause time was considerably shorter in each CPR segment with AC-CPR versus standard defibrillator operation (2.13 ± 0.99 sec vs. 10.93 ± 1.33, p < 0.0001), demonstrating effective use of AC-CPR with minimal training. Despite reduced chest compression interruption with AC-CPR, rescuer fatigue and perceived exertion did not differ in any CPR segment with standard defibrillator operation versus AC-CPR (p = 0.2-1.0). CONCLUSIONS: Preshock pause time is reduced by 80% utilizing a novel technology that employs automated analysis and charging during chest compression. Although chest compression pause time is reduced with the use of the new technology, participants do not excessively fatigue.

Protein expression in vascular endothelial cells obtained from human peripheral arteries and veins.

Studying molecular mechanisms of vascular endothelial function in humans is difficult in part because of limited access to arteries. Access to peripheral veins is more practical. We determined if differences in protein expression of endothelial cells (EC) collected from a peripheral artery are reflected in measurements made on EC obtained from peripheral veins. EC were collected from the brachial artery and an antecubital vein of 106 healthy adults (60 men and 46 women, age 18-77 years). Quantitative immunofluorescence was used to measure protein expression of endothelial nitric oxide synthase (eNOS), Ser-1177 phosphorylated eNOS, manganese superoxide dismutase, nitrotyrosine, xanthine oxidase and nuclear factor-kappaB p65. Protein expression in EC obtained from brachial artery and antecubital vein sampling was moderately to strongly related (r = 0.59-0.81, all p < 0.0001, mean r = 0.70). Moreover, differences between subgroups in the lowest and highest tertiles of protein expression in EC obtained from arterial samples were consistently reflected in EC obtained from venous collections. These findings indicate that interindividual and group differences in expression of several proteins involved in nitric oxide production, oxidant production, antioxidant defense and inflammatory signaling in EC obtained from brachial artery sampling are consistently reflected in EC obtained from venous samples. Thus, EC collected from peripheral veins may provide a useful surrogate for EC obtained from arteries for measurements of EC protein expression in humans.

Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase.

To determine whether impaired endothelium-dependent dilation (EDD) in older adults is associated with changes in the expression of major vasoconstrictor or vasodilator proteins in the vascular endothelium, endothelial cells (EC) were obtained from the brachial artery and peripheral veins of 56 healthy men, aged 18-78 yr. Brachial artery EC endothelin-1 (ET-1) [0.99 +/- 0.10 vs. 0.57 +/- 0.10 ET-1/human umbilical vein EC (HUVEC) intensity, P = 0.01] and serine 1177 phosphorylated endothelial nitric oxide synthase (PeNOS) (0.77 +/- 0.09 vs. 0.44 +/- 0.07 PeNOS/HUVEC intensity, P < 0.05) (quantitative immunofluorescence) were greater, and EDD (peak forearm blood flow to intrabrachial acetylcholine) was lower (10.2 +/- 0.9 vs. 14.7 +/- 1.7 ml.100 ml(-1).min(-1), P < 0.05) in older (n = 18, 62 +/- 1 yr) vs. young (n = 15, 21 +/- 1 yr) healthy men. EDD was inversely related to expression of ET-1 (r = -0.39, P < 0.05). Brachial artery EC eNOS expression did not differ significantly with age, but tended to be greater in the older men (young: 0.23 +/- 0.03 vs. older: 0.33 +/- 0.07 eNOS/HUVEC intensity, P = 0.08). In the sample with venous EC collections, EDD (brachial artery flow-mediated dilation) was lower (3.50 +/- 0.44 vs. 7.68 +/- 0.43%, P < 0.001), EC ET-1 and PeNOS were greater (P < 0.05), and EC eNOS was not different in older (n = 23, 62 +/- 1 yr) vs. young (n = 27, 22 +/- 1 yr) men. EDD was inversely related to venous EC ET-1 (r = -0.37, P < 0.05). ET-1 receptor A inhibition with BQ-123 restored 60% of the age-related impairment in carotid artery dilation to acetylcholine in B6D2F1 mice (5-7 mo, n = 8; 30 mo, n = 11; P < 0.05). ET-1 expression is increased in vascular EC of healthy older men and is related to reduced EDD, whereas ET-1 receptor A signaling tonically suppresses EDD in old mice. Neither eNOS nor PeNOS is reduced with aging. Changes in ET-1 expression and bioactivity, but not eNOS, contribute to vascular endothelial dysfunction with aging.

Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB.

Aging is associated with impaired vascular endothelial function, as indicated in part by reduced endothelium-dependent dilation (EDD). Decreased EDD with aging is thought to be related to vascular endothelial cell oxidative stress, but direct evidence is lacking. We studied 95 healthy men: 51 young (23+/-1 years) and 44 older (63+/-1 years). EDD (brachial artery flow-mediated dilation) was approximately 50% lower in older versus young men (3.9+/-0.3% versus 7.6+/-0.3%, P<0.01; n=42 older/n=51 young). Abundance of nitrotyrosine (quantitative immunofluorescence), an oxidatively modified amino acid and marker of oxidative stress, was higher in endothelial cells (ECs) obtained from the brachial artery (1.25+/-0.12 versus 0.61+/-0.11 nitrotyrosine intensity/human umbilical vein EC [HUVEC] intensity, P=0.01; n=11 older/n=11 young) and antecubital veins (0.55+/-0.04 versus 0.34+/-0.03, P<0.05; n=19 older/n=17 young) of older men. Flow-mediated dilation was inversely related to arterial EC nitrotyrosine expression (r=-0.62, P=0.01; n=22). In venous samples, EC expression of the oxidant enzyme NAD(P)H oxidase-p47(phox) was higher in older men (0.71+/-0.05 versus 0.57+/-0.05 NAD[P]H oxidase-p47(phox) intensity/HUVEC intensity, P<0.05; n=19 older/n=18 young), whereas xanthine oxidase and the antioxidant enzymes cytosolic and mitochondrial superoxide dismutase and catalase were not different between groups. Nuclear factor-kappaB p65, a component of the redox-sensitive nuclear transcription factor nuclear factor-kappaB, was elevated in both arterial (0.73+/-0.07 versus 0.53+/-0.05 NF-kappaB p65 intensity/HUVEC intensity, P<0.05; n=9 older/n=12 young) and venous (0.65+/-0.07 versus 0.34+/-0.05, P<0.01; n=13 older/n=15 young) EC samples of older men and correlated with nitrotyrosine expression (r=0.51, P<0.05 n=16). These results provide direct support for the hypothesis that endothelial oxidative stress develops with aging in healthy men and is related to reductions in EDD. Increased expression of NAD(P)H oxidase and nuclear factor-kappaB may contribute to endothelial oxidative stress with aging in humans.

Overweight and obese humans demonstrate increased vascular endothelial NAD(P)H oxidase-p47(phox) expression and evidence of endothelial oxidative stress.

BACKGROUND: Obesity may alter vascular endothelial cell protein expression (VECPE) of molecules that influence susceptibility to atherosclerosis. METHODS AND RESULTS: Quantitative immunofluorescence was performed on vascular endothelial cells collected from 108 men and women free of clinical disease who varied widely in adiposity (body mass index 18.4 to 36.7 kg/m2; total body fat 5.8 to 55.0 kg; waist circumference: 63.0 to 122.9 cm). All 3 expressions of adiposity were positively associated with VECPE of the oxidant enzyme subunit NAD(P)H oxidase-p47(phox) (part correlation coefficient [r(part)] 0.22 to 0.24, all P < 0.05) and the antioxidant enzyme catalase (r(part) = 0.71 to 0.75, all P < 0.001). Total body fat was positively associated with VECPE of nitrotyrosine (r(part) = 0.36, P = 0.003), a marker of protein oxidation, and, in men, with Ser1177-phosphorylated endothelial nitric oxide synthase (r(part) = 0.46, P = 0.02), an activated form of endothelial nitric oxide synthase. Overweight/obese subjects (body mass index > or = 25 kg/m2) had 35% to 130% higher VECPE of NAD(P)H oxidase-p47(phox), nitrotyrosine, catalase, and the cytosolic antioxidant CuZn superoxide dismutase (all P < 0.05), as well as a 56% greater VECPE of the potent local vasoconstrictor endothelin-1 (P = 0.05) than normal-weight subjects (body mass index < 25 kg/m2). Nuclear factor-kappaB protein expression was approximately 60% to 100% greater in the most obese adults than in the leanest adults (P < or = 0.01). These relations were independent of sex but were selectively reduced after accounting for the influence of plasma C-reactive protein, fasting glucose-insulin metabolism, or serum triglycerides. CONCLUSIONS: Compared with their normal-weight peers, overweight and obese adults demonstrate increased vascular endothelial expression of NAD(P)H oxidase-p47(phox) and evidence of endothelial oxidative stress, with selective compensatory upregulation of antioxidant enzymes and Ser1177-phosphorylated endothelial nitric oxide synthase. Endothelin-1 and nuclear factor-kappaB protein expression also appear to be elevated in obese compared with lean adults. These findings may provide novel insight into the molecular mechanisms linking obesity to increased risk of clinical atherosclerotic diseases in humans.

Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery.

OBJECTIVE: Reactive hyperemia is the compensatory increase in blood flow that occurs after a period of tissue ischemia, and this response is blunted in patients with cardiovascular risk factors. The predictive value of reactive hyperemia for cardiovascular events in patients with atherosclerosis and the relative importance of reactive hyperemia compared with other measures of vascular function have not been previously studied. METHODS AND RESULTS: We prospectively measured reactive hyperemia and brachial artery flow-mediated dilation by ultrasound in 267 patients with peripheral arterial disease referred for vascular surgery (age 66+/-11 years, 26% female). Median follow-up was 309 days (range 1 to 730 days). Fifty patients (19%) had an event, including cardiac death (15), myocardial infarction (18), unstable angina (8), congestive heart failure (6), and nonhemorrhagic stroke (3). Patients with an event were older and had lower hyperemic flow velocity (75+/-39 versus 95+/-50 cm/s, P=0.009). Patients with an event also had lower flow-mediated dilation (4.5+/-3.0 versus 6.9+/-4.6%, P<0.001), and when these 2 measures of vascular function were included in the same Cox proportional hazards model, lower hyperemic flow (OR 2.7, 95% CI 1.2 to 5.9, P=0.018) and lower flow-mediated dilation (OR 4.2, 95% CI: 1.8 to 9.8, P=0.001) both predicted cardiovascular events while adjusting for other risk factors. CONCLUSIONS: Thus, lower reactive hyperemia is associated with increased cardiovascular risk in patients with peripheral arterial disease. Furthermore, flow-mediated dilation and reactive hyperemia incrementally relate to cardiovascular risk, although impaired flow-mediated dilation was the stronger predictor in this population. These findings further support the clinical relevance of vascular function measured in the microvasculature and conduit arteries in the upper extremity.

Cardiac rhythm analysis during ongoing cardiopulmonary resuscitation using the Analysis During Compressions with Fast Reconfirmation technology.

BACKGROUND: Pauses in chest compressions (CCs) have a negative association with survival from cardiac arrest. Electrocardiographic (ECG) rhythm analysis and defibrillator charging are significant contributors to CC pauses. OBJECTIVE: Accuracy of the Analysis During Compressions with Fast Reconfirmation (ADC-FR) algorithm, which features automated rhythm analysis and charging during CCs to reduce CC pauses, was retrospectively determined in a large database of ECGs from 2701 patients with out-of-hospital cardiac arrest. METHODS: The ADC-FR algorithm generated a total of 7264 advisories, of which 3575 were randomly assigned to a development data set and 3689 to a test data set. With ADC-FR, a high-pass digital filter is used to remove CC artifacts, while the underlying ECG rhythm is automatically interpreted. When CCs are paused at the end of the 2-minute cardiopulmonary resuscitation interval, a 3-second reconfirmation analysis is performed using the artifact-free ECG to confirm the shock/no-shock advisory. The sensitivity and specificity of the ADC-FR algorithm in correctly identifying shockable/nonshockable rhythms during CCs were calculated. RESULTS: In both data sets, the accuracy of the ADC-FR algorithm for each ECG rhythm exceeded the recommended performance goals, which apply to a standard artifact-free ECG analysis. Sensitivity and specificity were 97% and 99%, respectively, for the development data set and 95% and 99% for the test data set. CONCLUSION: The ADC-FR algorithm is highly accurate in discriminating shockable and nonshockable rhythms and can be used to reduce CC pauses.

Impaired flow-mediated dilation with age is not explained by L-arginine bioavailability or endothelial asymmetric dimethylarginine protein expression.

Aging is associated with a decline in vascular endothelial function, manifesting in part as impaired flow-mediated arterial dilation (FMD), but the underlying mechanisms are uncertain. Impaired FMD may be mediated in part by a decrease in synthesis of nitric oxide by endothelial nitric oxide synthase, and in clinical populations this has been attributed to competitive inhibition of l-arginine binding sites by asymmetric dimethylarginine (ADMA). If this mechanism is involved in the age-associated decline in FMD, increasing l-arginine concentration may swing the competitive balance in favor of l-arginine binding, restoring nitric oxide synthesis, and enhancing FMD in older humans. To test this hypothesis, we measured FMD (brachial ultrasound) in 10 younger (21 +/- 1 yr) and 12 older healthy men and women (60 +/- 2 yr) following infusion of vehicle or vehicle + l-arginine. Baseline FMD in the older subjects was only approximately 60% of that in the younger subjects (P = 0.002). l-Arginine did not significantly increase FMD in either group despite 23-fold (older) and 19-fold (younger) increases in plasma l-arginine concentrations (P < 0.0001 vs. control). Protein expression (immunofluorescence) in vascular endothelial cells showed that ADMA and the enzyme isoform that controls its degradation, dimethylarginine dimethylaminohydrolase II, were not different in the younger and older subjects. Endothelium-independent vasodilation (sublingual nitroglycerine) was not different between age groups or conditions. We conclude that acutely increasing plasma concentrations of l-arginine do not significantly improve brachial artery FMD in healthy older subjects and thus does not restore the age-associated loss of FMD. Together with the finding that endothelial cell ADMA protein expression was not increased in older adults, these findings suggest that competitive inhibition of l-arginine binding sites on endothelial nitric oxide synthase by ADMA is not an important mechanism contributing to impaired conduit artery endothelium-dependent dilation with aging in healthy humans.

Amplitude-spectral area and chest compression release velocity independently predict hospital discharge and good neurological outcome in ventricular fibrillation out-of-hospital cardiac arrest.

OBJECTIVE: In out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) the frequency-based waveform characteristic, amplitude-spectral area (AMSA) is associated with hospital discharge and good neurological outcome, yet AMSA is also known to increase in response to chest compressions (CC). In addition to rate and depth, well performed CC provides good chest recoil without leaning, reflected in the release velocity (RV). We hypothesized that AMSA is associated with hospital discharge and good neurological outcome independent of CC quality. METHODS: OHCA patients (age ≥ 18), with initial rhythm of VF from an Utstein-Style database were analyzed. AMSA was measured prior to each shock, and averaged for each subject (AMSA-avg). Primary endpoint was hospital discharge and secondary endpoint was a good neurological outcome. Univariate and stepwise multivariable logistic regression, and receiver-operator-characteristic (ROC) analyses were performed. Factors analyzed were age, sex, witnessed status, time from dispatch to monitor/defibrillator application, number of shocks, first shock AMSA (AMSA1), AMSA-avg, averaged pre-shock pause, CC rate, depth, and RV. RESULTS: 140 subjects were analyzed. Hospital discharge was 31% and with good neurological outcome in 24% (77% of those discharged). AMSA-avg (p < 0.001), RV (p = 0.002), and age (p = 0.029) were independently associated with hospital discharge, with a non-significant trend for witnessed status (p = 0.069), with AUC = 0.846 for the multivariate model. For good neurological outcome, AMSA-avg (p = 0.001) and RV (p = 0.001) remained independently significant, with AUC = 0.782. CONCLUSION: In OHCA with an initial rhythm of VF, AMSA-avg and CC RV are both highly and independently associated with hospital discharge and good neurological outcome.

Association of amplitude spectral area of the ventricular fibrillation waveform with survival of out-of-hospital ventricular fibrillation cardiac arrest.

BACKGROUND: Previous investigations of out-of-hospital cardiac arrest (OHCA) have shown that the waveform characteristic amplitude spectral area (AMSA) can predict successful defibrillation and return of spontaneous circulation (ROSC) but has not been studied previously for survival. OBJECTIVES: To determine whether AMSA computed from the ventricular fibrillation (VF) waveform is associated with pre-hospital ROSC, hospital admission, and hospital discharge. METHODS: Adults with witnessed OHCA and an initial rhythm of VF from an Utstein style database were studied. AMSA was measured prior to each shock and averaged for each subject (AMSA-avg). Factors such as age, sex, number of shocks, time from dispatch to monitor/defibrillator application, first shock AMSA, and AMSA-avg that could predict pre-hospital ROSC, hospital admission, and hospital discharge were analyzed by logistic regression. RESULTS: Eighty-nine subjects (mean age 62 ± 15 years) with a total of 286 shocks were analyzed. AMSA-avg was associated with pre-hospital ROSC (p = 0.003); a threshold of 20.9 mV-Hz had a 95% sensitivity and a 43.4% specificity. Additionally, AMSA-avg was associated with hospital admission (p < 0.001); a threshold of 21 mV-Hz had a 95% sensitivity and a 54% specificity and with hospital discharge (p < 0.001); a threshold of 25.6 mV-Hz had a 95% sensitivity and a 53% specificity. First-shock AMSA was also predictive of pre-hospital ROSC, hospital admission, and discharge. Time from dispatch to monitor/defibrillator application was associated with hospital admission (p = 0.034) but not pre-hospital ROSC or hospital discharge. CONCLUSIONS: AMSA is highly associated with pre-hospital ROSC, survival to hospital admission, and hospital discharge in witnessed VF OHCA. Future studies are needed to determine whether AMSA computed during resuscitation can identify patients for whom continuing current resuscitation efforts would likely be futile.

Resumption of chest compressions after successful defibrillation and risk for recurrence of ventricular fibrillation in out-of-hospital cardiac arrest.

BACKGROUND: Prior investigation of out-of-hospital cardiac arrest has raised the concern that ventricular fibrillation (VF) recurrence may be triggered by chest compression (CC) resumption. We investigated predictors of VF recurrence after defibrillation, including timing of CC resumption. METHODS AND RESULTS: Patients with witnessed out-of-hospital cardiac arrest and initial rhythm of VF from an Utstein-style database were analyzed. For each shock that defibrillated VF, CC resumption and VF recurrence times were determined. Shocks were classified according to postshock rhythm. Factors (age, sex, time from dispatch to monitor/defibrillator application, and CC resumption) that could predict VF recurrence were analyzed. CC resumption was categorized into groups: CC1, 1 to 5 seconds; CC2, 6 to 10 seconds; CC3, 11 to 30 seconds; and CC4, >30 seconds. Eighty-eight subjects were analyzed, with a total of 285 shocks, with 226 shocks that achieved asystole (n=102), organized rhythm (n=120), or monomorphic ventricular tachycardia (n=4). After a successful shock, CC resumption occurred at a median (interquartile range) of 8 (5-18) seconds. VF recurred after 166 shocks (74%) and recurred within 30 seconds in 69 shocks. There was no significant relationship between VF recurrence and factors analyzed including CC resumption time, nor stratified by postshock rhythm. The hazard ratios (HRs) for VF recurrence within 30 seconds for later CC groups (CC2, CC3, and CC4) relative to early CC resumption (CC1) were as follows: HR(CC2)=1.05 (P=0.9); HR(CC3)=1.75 (P=0.1); and HR(CC4)=0.67 (P=0.4). CONCLUSIONS: VF recurrence within 30 seconds of a defibrillatory shock was not dependent on timing of CC resumption in patients with witnessed arrest and initial rhythm of VF.

Habitually exercising older men do not demonstrate age-associated vascular endothelial oxidative stress.

We tested the hypothesis that older men who perform habitual aerobic exercise do not demonstrate age-associated vascular endothelial oxidative stress compared with their sedentary peers. Older exercising men (n=13, 62±2 years) had higher (P<0.05) physical activity (79±7 vs. 30±6 MET hours per week) and maximal exercise oxygen consumption (42±1 vs. 29±1 mL kg(-1) per minute) vs. sedentary men (n=28, 63±1 years). Brachial artery flow-mediated dilation (FMD), a measure of vascular endothelial function, was greater (P<0.05) in the exercising vs. sedentary older men (6.3±0.5 vs. 4.9±0.4%Δ) and not different than young controls (n=20, 25±1 years, 7.1±0.5%Δ). In vascular endothelial cells sampled from the brachial artery, nitrotyrosine, a marker of oxidative stress, was 51% lower in the exercising vs. sedentary older men (0.38±0.06 vs. 0.77±0.10 AU). This was associated with lower endothelial expression of the oxidant enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47(phox) subunit, 0.33±0.05 vs. 0.61±0.09 AU) and the redox-sensitive transcription factor nuclear factor kappa B (NFκB) (p65 subunit, 0.36±0.05 vs. 0.72±0.09 AU). Expression of the antioxidant enzyme manganese superoxide dismutase (SOD) (0.57±0.13 vs. 0.30±0.04 AU) and activity of endothelium-bound extracellular SOD were greater (6.4±0.5 vs. 5.0±0.6 U mL(-1) per minute) in the exercising men (both P<0.05), but differences no longer were significant after correcting for adiposity and circulating metabolic factors. Overall, values for the young controls differed with those for the sedentary, but not the exercising older men. Older men who exercise regularly do not demonstrate vascular endothelial oxidative stress, and this may be a key molecular mechanism underlying their reduced risk of cardiovascular diseases.

Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women.

CONTEXT AND OBJECTIVE: Estrogen receptor alpha (ER alpha), a potent transcription factor expressed in vascular endothelial cells, plays a key role in regulating vascular function and health. We determined whether vascular endothelial cell expression of ER alpha is influenced by estrogen status and is related to vascular endothelial function in healthy women. METHODS: ER alpha protein expression was measured (quantitative immunofluorescence) in endothelial cells from peripheral veins of 16 healthy, premenopausal women during the early follicular (EF) and late follicular (LF) phases of the menstrual cycle and 17 estrogen-deficient postmenopausal women. Endothelial-dependent dilation (EDD; brachial artery flow-mediated dilation) and endothelial nitric oxide synthase (eNOS) expression and activation were also measured in a subgroup of women. RESULTS: In premenopausal women (n = 10), ER alpha expression was 30% lower (P < 0.001) during the EF (low estrogen) compared with the LF (high estrogen) phase of the menstrual cycle. In postmenopausal women, ER alpha expression was 33% lower (P < 0.001) compared with the LF phase of the menstrual cycle in premenopausal women. ER alpha expression was strongly related (r = 0.67; P < 0.001) to EDD, which was reduced in postmenopausal women. ER alpha abundance was positively related to expression of eNOS (r = 0.54; P = 0.009; n = 21) and ser1177 phosphorylated eNOS (r = 0.59; P = 0.006; n = 20). CONCLUSIONS: These results provide the first evidence that expression of ER alpha in vascular endothelial cells is modulated by estrogen status and may be a key determinant of vascular endothelial function in healthy pre- and postmenopausal women. ER alpha expression may influence vascular endothelial function in women by affecting protein levels and activation of eNOS.

Habitual aerobic exercise is associated with smaller femoral artery intima-media thickness with age in healthy men and women.

BACKGROUND: Femoral artery intima-media thickness (IMT), an independent predictor of atherosclerotic disease risk, increases with age in sedentary adults. It is not known whether regular aerobic exercise modulates femoral IMT with ageing. METHODS AND RESULTS: Study 1: Femoral IMT was measured in 173 sedentary, moderately active, and endurance-trained young (20-39 years), middle-aged (40-59 years) and older (60-79 years) men. IMT increased with age in all activity groups (P<0.001). However, IMT was 20-27% smaller in age-matched, endurance-trained compared with sedentary men (P<0.001), and the age-associated increase in IMT was 33% smaller in endurance-trained compared with sedentary men (+0.32 versus +0.45 mm). There was a trend for the IMT to be smaller in moderately active compared with sedentary older men, and the age-associated increase in IMT was 37% smaller in moderately active than sedentary men (+0.28 mm). Study 2: Among 74 premenopausal and postmenopausal sedentary or endurance-trained women, IMT was higher (P<0.001) in postmenopausal compared with premenopausal women regardless of activity status. However, IMT was 15% smaller in endurance-trained compared with sedentary postmenopausal women (P<0.001), and the premenopausal to postmenopausal difference in IMT was approximately 45% smaller in endurance-trained compared with sedentary women (+0.13 versus +0.23 mm). CONCLUSIONS: Femoral IMT increases with age even in habitually exercising adults. However, the age-associated increase and absolute level of IMT are smaller in middle-aged and older adults who perform regular aerobic-endurance exercise, and may contribute to their lower incidence of atherosclerotic disease.