Effects of acute and sub-acute hypobaric hypoxia on oxidative stress: a field study in the Alps.

PURPOSE: High altitude results in lower barometric pressure and hence partial pressure of O2 decrease can lead to several molecular and cellular changes, such as generation of reactive oxygen species (ROS). Electron Paramagnetic Resonance technique was adopted in the field, to evaluate the effects of acute and sub-acute hypobaric hypoxia (HH) on ROS production by micro-invasive method. Biological biomarkers, indicators of oxidative stress, renal function and inflammation were investigated too. METHODS: Fourteen lowlander subjects (mean age 27.3 ± 5.9 years) were exposed to HH at 3269 m s.l. ROS production, related oxidative damage to cellular components, systemic inflammatory response and renal function were determined through blood and urine profile performed at 1st, 2nd, 4th, 7th, and 14th days during sojourn. RESULTS: Kinetics of changes during HH exposition showed out significant (range p < 0.05-0.0001) increases that at max corresponds to 38% for ROS production rate, 140% for protein carbonyl, 44% for lipid peroxidation, 42% for DNA damage, 200% for inflammatory cytokines and modifications in renal function (assessed by neopterin concentration: 48%). Conversely, antioxidant capacity significantly (p < 0.0001) decreased - 17% at max. CONCLUSION: This 14 days in-field study describes changes of oxidative-stress biomarkers during HH exposure in lowlanders. The results show an overproduction of ROS and consequent oxidative damage to protein, lipids and DNA with a decrease in antioxidant capacity and the involvement of inflammatory status and a transient renal dysfunction. Exposure at high altitude induces a hypoxic condition during acute and sub-acute phases accompanied by molecular adaptation mechanism indicating acclimatization.

P260Right cardiac chambers remodeling in marathon and ultra-trail athletes detected by speckle-tracking echocardiography.

BACKGROUND: Strenuous and chronic exercise training can have detrimental effects on cardiac morphology and function. Our aim was to evaluate the cardiac adaptation between 2 different specialties' endurance athletes: marathon runners (M) and ultra-trailers (UT). METHODS: 47 M (age 45±7, men 32; training: 18 (9-53) years*days/week), 41 UT (age 42±9, men 38, training: 30 (15-66) years*days/week) were submitted in rest condition to conventional 2D echocardiography and Speckle-Tracking echo (STE) (Beyond Diogenes 2.0, AMID) during agonistic season and compared with 15 age matched sedentary individuals (S) (age 43±6, men 10). RESULTS: Left ventricle (LV) global longitudinal strain (GLS) and global radial strain (GRS) were increased in M and UT compared to S (see table) without differences in LV anatomy and function. Right ventricle (RV) end-diastolic area (p=0.026), fractional area changing (p=0.008) and RV GLS were increased in UT compared to M. Moreover UT showed larger right atrium (RA) volume compared to M (p=0.03) and S (p=0.003). RA GLS was reduced in UT compared to M while the RA Global Circumferential Strain was significantly increased in UT. After adjusted for age, sex and HR as covariates, UT showed a reduced RA GLS (OR 0.907; CI 0.856-0.961) and increased RV FAC (OR 1.172; CI: 1.044-1.317) compared to M; while when compared to S subjects, UT showed increased RA volume (OR 1.048; CI 1.002-1.096) and RV GLS (OR 0.667; CI 0.490-0.907). CONCLUSION: UT showed higher RV and RA morphological and functional remodeling in comparison with M. 2D-STE is a useful tool to investigate the deformation dynamic in different sport specialties. Further studies will be necessary to clarify the long-term consequences for cardiac health due to myocardial perturbations.MUTSpLV GLS-28.59±3.43*-27.64±4.18*-24.82±4.53<0.05LV GRS69.85±8.94*66.59±11.19*56.27±16.25<0.001RV GLS-25.60±10.54-30.41±4.38*-27.10±4.64<0.05RA GLS37.15±13.4931.65±9.60*35.37±9.99<0.05RA GCS17.46±6.4222.28±8.97*23.37±6.47<0.01.

Acute effects of different degrees of ultra-endurance exercise on systemic inflammatory responses.

BACKGROUND: Intense physical stress might promote inflammatory responses, whereas a regular physical exercise has positive influence. Little is known on the acute metabolic and inflammatory responses to different levels of strenuous exercise in trained athletes. AIM: To compare the short-term effect of two different ultra-endurance competitions on the inflammatory profile in male triathletes. METHODS: We studied 14 Ironman (IR) and 13 Half Ironman (HIR) before and after their own specific race. We assessed body composition and measured blood cells, lipids, iron metabolism and plasma levels of some acute-phase cytokines and inflammatory markers. RESULTS: After the race, IR showed reduced total body water and fat-free mass, not related with the duration of exercise, and increased white cells and platelets; high-density lipoprotein levels also increased. IR, but not HIR, showed reduced iron levels, increased ferritin and transferrin, reduced % saturated transferrin. HIR showed higher basal interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-10, IL-1ß than IR; however, the post-performance rise was greater in IR. Irisin increased only in HIR and osteocalcin decreased in IR. In the whole study group, delta of white blood cells was directly related with delta of monocyte chemoattractant protein 1, and Δ ferritin was inversely related with Δosteocalcin. CONCLUSIONS: A single ultra-endurance competition induces an inflammatory response depending on the duration of physical effort, with increased acute-phase cytokines, and an altered iron metabolism. Irisin, whose biological meaning is still uncertain, seems to be associated with acute variations of some metabolic parameters.

Cardiovascular function in healthy Himalayan high-altitude dwellers.

BACKGROUND: Residents of the Himalayan valleys uniquely adapted to their hypoxic environment in terms of pulmonary vasculature, but their systemic vascular function is still largely unexplored. The aim of the study was to investigate vascular function and structure in rural Sherpa population, permanently living at high altitude in Nepal (HA), in comparison with control Caucasian subjects (C) living at sea level. METHODS AND RESULTS: 95 HA and 64 C were enrolled. Cardiac ultrasound, flow-mediated dilation (FMD) of the brachial artery, carotid geometry and stiffness, and aortic pulse wave velocity (PWV) were performed. The same protocol was repeated in 11 HA with reduced FMD, after 1-h 100% O2 administration. HA presented lower FMD (5.18 ± 3.10 vs. 6.44  ±  2.91%, p = 0.02) and hyperemic velocity than C (0.61 ± 0.24 vs. 0.75 ± 0.28 m/s, p = 0.008), while systolic pulmonary pressure was higher (29.4 ± 5.5 vs. 23.6 ± 4.8 mmHg, p < 0.0001). In multiple regression analysis performed in HA, hyperemic velocity remained an independent predictor of FMD, after adjustment for baseline brachial artery diameter, room temperature and pulse pressure, explaining 8.7% of its variance. On the contrary, in C brachial artery diameter remained the only independent predictor of FMD, after adjustment for confounders. HA presented also lower carotid IMT than C (0.509 ± 0.121 vs. 0.576 ± 0.122 mm, p < 0.0001), higher diameter (6.98 ± 1.07 vs. 6.81 ± 0.85 mm, p = 0.004 adjusted for body surface area) and circumferential wall stress (67.6 ± 13.1 vs. 56.4 ± 16.0 kPa, p < 0.0001), while PWV was similar. O2 administration did not modify vascular variables. CONCLUSIONS: HA exhibit reduced NO-mediated dilation in the brachial artery, which is associated to reduced hyperemic response, indicating microcirculatory dysfunction. A peculiar carotid phenotype, characterized by reduced IMT and enlarged diameter, was also found.

Head-to-head comparison of indices of left ventricular contractile reserve assessed by high-dose dobutamine stress echocardiography in idiopathic dilated cardiomyopathy: five-year follow up.

OBJECTIVE: To compare head to head the indices of left ventricular contractile reserve assessed by high-dose dobutamine in the five-year prognosis of patients with idiopathic dilated cardiomyopathy. DESIGN AND SETTING: Prospective study in a tertiary care centre. PATIENTS: 63 consecutive patients with idiopathic dilated cardiomyopathy. INTERVENTIONS: High-dose dobutamine stress echocardiography was performed in progressive stages lasting 5 min each. Wall motion score index, ejection fraction, cardiac power output and end systolic pressure to volume ratio were evaluated as indices of left ventricular contractility. MAIN OUTCOME MEASURE: Five-year cardiac mortality. RESULTS: During the follow up of 59 patients, 27 (45.8%) died of cardiac causes. According to Kaplan-Meier and receiver operating characteristic analyses all indices of contractile reserve differentiated patients with respect to cardiac death. Wall motion score index achieved the best separation (log rank 21.75, p < 0.0001, area under the curve 0.84), followed by change in ejection fraction (log rank 11.25, p = 0.0008, area under the curve 0.79), end systolic pressure to volume ratio (log rank 14.32, p = 0.0002, area under the curve 0.75) and cardiac power output (log rank 9.84, p = 0.0017, area under the curve 0.71). Cox's regression model identified wall motion score index as the only independent predictor of cardiac death. CONCLUSIONS: These data show that all examined indices of left ventricular contractile reserve are predictive of five-year prognosis, but change in wall motion score index may have the greatest prognostic potential.

Prognostic significance of the dobutamine echocardiography test in idiopathic dilated cardiomyopathy.

Dobutamine stress echo provides potentially useful information on idiopathic dilated cardiomyopathy (IDC). From February 1, 1997, to October 1, 1999, 186 patients (131 men and 55 women, mean age 56 +/- 12 years) with IDC, ejection fraction <35%, and angiographically normal coronary arteries were studied by high-dose (up to 40 micro/kg/min) dobutamine echo in 6 centers, all quality controlled for stress echo reading. In all patients, wall motion score index (WMSI) (from 1 = normal to 4 = dyskinetic in a 16- segment model of the left ventricle) was evaluated by echo at baseline and peak dobutamine. One hundred eighty-four patients were followed up (mean 15 +/- 13 months) and only cardiac death was considered as an end point. There were 29 cardiac deaths. Significant parameters for survival prediction at univariate analysis are: DeltaWMSI (chi-square 20.1; p <0.0000), New York Heart Association (NYHA) class (chi-square 17.57; p <0.0000), rest ejection fraction (chi-square 10.41; p = 0.0013), angiotensin-converting enzyme inhibitors (chi-square 8.23; p = 0.0041), and hypertension (chi-square 8.08, p = 0.0045). In the multivariate stepwise analysis only DeltaWMSI and NYHA were independent predictors of outcome (DeltaWMSI = hazard ratio 0.02, p < 0.0000; NYHA class = hazard ratio 3.83, p < 0.0000). Kaplan-Meier survival estimates showed a better outcome for patients with a large inotropic response (DeltaWMSI > or =0.44, a cutoff identified by receiver-operating characteristic curves analysis) than for those with a small or no myocardial inotropic response to dobutamine (93.6% vs 69.4%, p = 0.00033). Thus, in patients with IDC, an extensive contractile reserve identified by high-dose dobutamine stress echocardiography is associated with a better survival.

Value of transthoracic echocardiography in the diagnosis of pulmonary embolism: results of a prospective study in unselected patients.

PURPOSE: Echocardiography is advocated by some as a useful diagnostic test for patients with suspected pulmonary embolism (PE), but its diagnostic accuracy is unknown. The present study was undertaken to determine prospectively the sensitivity and specificity of transthoracic echocardiography in the diagnosis of PE. SUBJECTS AND METHODS: We examined 110 consecutive patients with suspected PE. The study protocol included assessment of clinical probability, echocardiography, and perfusion lung scanning. Pulmonary angiography was performed in all patients with abnormal scans. As echocardiographic criteria to diagnose acute PE, we used the presence of any two of the following: right ventricular (RV) hypokinesis, RV end-diastolic diameter >27 mm (without RV wall hypertrophy), or tricuspid regurgitation velocity >2.7 m/sec. Clinical estimates of PE served as pretest probabilities in calculating, after echocardiography, the posttest probabilities of PE. RESULTS: Pulmonary angiography confirmed PE in 43 (39%) of 110 patients. Echocardiographic diagnostic criteria for PE yielded a sensitivity of 56% and a specificity of 90%. For pretest probabilities of 10%, 50%, and 90%, the posttest probabilities of PE conditioned by a positive echocardiogram were 38%, 85%, and 98%, respectively. The posttest probabilities of PE conditioned by a negative echocardiogram were 5%, 33%, and 81%, respectively. CONCLUSIONS: In unselected patients with suspected PE, transthoracic echocardiography fails to identify some 50% of patients with angiographically proven PE. Although echocardiographic findings of RV strain, paired with a high clinical likelihood, support a diagnosis of PE, the transthoracic echocardiography has to have a better sensitivity to be used as a screening test to rule out PE.

New technologies in stress echocardiography.

Stress echo has become the preferred theater where innovative technologies are first tested. The new technologies address, in different ways, various physiological targets: more quantitative assessment of the regional wall thickening (by anatomical M-mode); operator-independent assessment of global and regional systolic function (by anatomic boundary detection and color kinesis); tissue composition and physiologic state (by tissue characterization); transmural stratification of myocardial (subendocardial) function (by tissue Doppler imaging); more quantitative evaluation of contrast-enhanced myocardial perfusion (by harmonic imaging). All new emerging techniques aim to improve display and communication among physicians by translating the description of function into numbers and/or colors. However, cardiologists have to be aware that due the pro-technology bias of modern medicine, we, as physicians, are encouraged to trust, to use (and to buy) technologies far before their clinical incremental value has been shown.

Madness and method in stress echo reading.

AIM: To assess whether 'eye education' through short-term, high-intensity joint reading sessions may improve diagnostic accuracy and inter-observer agreement among beginners. METHODS AND RESULTS: Seventeen cardiologists with absent to minimal (<100 studies performed) previous stress echo experience independently and blindly read 18 stress echo studies, nine at the beginning ('pre-training' set) and nine at the end ('post-training' set) of a 2 day stress echo school which included a joint reading session of 50 tapes. The two sets were balanced as far as type of stress and image quality. The 17 observers had an average accuracy score of 51+/-16.4 before and 64.3+/-8.7% after the training (P<0.005). Concordant (i.e. >14 readers giving the same response) interpretation occurred in three out of nine studies before and in eight out of nine studies after the training (33% vs 88%, P<0.01). Kappa values went from 0.14 (poor) before to 0.39 (fair, close to moderate) after the training. CONCLUSION: Short-term, high-intensity dedicated training in stress echo, with joint reading sessions and consensus development of reading criteria significantly increased accuracy and markedly reduced the inter-observer variability in the reading of stress echoes by beginners. If there is a Shakespearean madness in stress echo reading, 'yet there is a method in't' (Hamlet, II, II, 205-206).

The impact of second harmonic imaging on stress echocardiography reading.

BACKGROUND: Noncontrast harmonic significantly improves overall image quality in echocardiography. The aim of this study was to assess whether harmonic imaging, without contrast, impacts on interobserver variability and diagnostic accuracy of "beginners" in stress echocardiography. METHODS: Images at rest and peak stress were obtained in digitized format in 15 consecutive patients (10 males, 5 females, mean age 66 +/- 9 years) and analyzed by 5 inexperienced observers (stress echo beginners) who were blinded to the imaging modality (standard versus harmonic imaging). Each observer graded the image quality as 1 = uninterpretable up to 5 = excellent, in a total of 240 segments. RESULTS: The mean image quality per segment was 2.9 for conventional technology and increased up to 3.6 for harmonic imaging (p < 0.001). The interobserver agreement (> or = 4 out of 5 readers) rose from 46 to 60%. The percentage of uninterpretable segments was 7.5% at rest and 8.9% at peak stress of conventional imaging, and decreased to 4.6 and 6.5%, respectively (p < 0.05) by second harmonic technology. The unanimous reading of two additional independent expert observers was arbitrarily assumed to be the "gold standard" to verify the accuracy of reading of the 5 beginners. The 5 beginners showed poor diagnostic accuracy with fundamental imaging (73%), and they did not improve with second harmonic imaging (70%, NS vs fundamental). CONCLUSIONS: Noncontrast second harmonic imaging improves image quality over conventional imaging. The improved quality of the image deflated interobserver variability but did not determine per se an improvement in the diagnostic accuracy of nonexperienced readers.

Autonomic and hemodynamic responses to insulin in lean and obese humans.

To study the acute effects of insulin on autonomic control of cardiac function, we performed spectral analysis of heart rate variability and measured cardiac dynamics (by two-dimensional echocardiography) in 18 obese (BMI = 35 +/- 1 kg.m-2) and 14 lean (BMI = 24 +/- 1 kg.m-2) subjects in the basal state and in response to physiological hyperinsulinemia (1 mU.min-1.kg-1 insulin clamp). In the lean group, insulin promptly (within 20 min) and consistently depressed spectral powers, both in the low-frequency and high-frequency range. These changes were twice as large as accounted for by the concomitant changes in heart rate (68 +/- 2 to 70 +/- 2 beats/min). At the end of the 2-h clamp, stroke volume (67 +/- 4 to 76 +/- 9 ml.min-1) and cardiac output (4.45 +/- 0.21 to 5.06 +/- 0.55 l.min-1) rose, whereas peripheral vascular resistance fell. The low-to-high frequency ratio increased from 1.7 +/- 0.2 to 2.3 +/- 0.3 (P < 0.01), indicating sympathetic shift of autonomic balance. In the obese group, all basal spectral powers were significantly lower (by 40% on average) than in the lean group, and were further reduced by insulin administration. The low-to-high frequency ratio was higher than in controls at baseline (2.4 +/- 0.4, P < 0.03), and failed to increase after insulin (2.2 +/- 0.3, P = ns). Furthermore, obesity was associated with higher resting stroke volume (89 +/- 5 vs. 67 +/- 4 ml.min-1, P < 0.01) and cardiac output (6.01 +/- 0.31 vs. 4.45 +/- 0.21 l.min-1, P = 0.001) but lower peripheral vascular resistance (15.1 +/- 0.8 vs. 19.2 +/- 1.1 mmHg.min.L-1, P = 0.002), whereas mean arterial blood pressure was similar to control (90 +/- 2 vs. 86 +/- 2 mmHg, P = not significant). We conclude that physiological hyperinsulinemia causes acute desensitization of sinus node activity to both sympathetic and para-sympathetic stimuli, sympathetic shift of autonomic balance, and a high-output, low-resistance hemodynamic state. In the obese, these changes are already present in the basal state, and may therefore be linked with chronic hyperinsulinemia.

Assessment of coronary reserve by transoesophageal Doppler echocardiography. Direct comparison between different modalities of dipyridamole and adenosine administration.

BACKGROUND: This study was undertaken to compare the coronary vasodilator response to different application modalities of intravenous vasodilators, in order to identify the optimal pharmacological protocol for the evaluation of coronary reserve by means of transoesophageal Doppler echocardiography. METHODS: Blood flow velocity in the left anterior descending artery, coronary vascular resistance and left main coronary artery cross-sectional area were assessed by transoesophageal echo-Doppler during an i.v. adenosine bolus (5 mg), a 5-min adenosine infusion (infusion rate 140 micrograms. kg-1 min-1), and low (0.56 mg.kg-1. 4 min-1), and high-dose (0.84 mg.kg-1.9 min-1) dipyridamole infusions in 10 healthy normals (Group 1) and in 20 patients (Group 2) with either coronary microvascular disease (11 patients) or coronary artery disease (nine patients). RESULTS: In both groups, the highest flow velocity and the lowest coronary vascular resistance were observed during the adenosine infusion. Flow velocity values and indices of coronary vasodilator capacity observed after the adenosine bolus and the high-dose dipyridamole infusion were very close to those obtained during the adenosine infusion, especially in Group 1. Coronary flow velocity was lower and coronary vascular resistance higher after low-dose dipyridamole, significantly in Group 2. The maximal flow response to the adenosine bolus was observed within a few seconds after the injection, and was very short. The peak response to the adenosine infusion was observed 57 +/- 27 s after its start. The coronary flow velocity response to dipyridamole was dose dependent and differed between Groups 1 and 2. CONCLUSION: In combination with transoesophageal Doppler echocardiography, a short-lasting adenosine infusion at a rate of 140 micrograms.kg-1.min-1 seems to be preferable to an adenosine bolus and dipyridamole infusion. The effect of the bolus is too short for an accurate measurement of coronary flow velocity, while the dipyridamole infusion, especially at a low dose, induces a submaximal vasodilator response.

Mechanisms of coronary flow reserve impairment in human hypertension. An integrated approach by transthoracic and transesophageal echocardiography.

The purpose of this study was to investigate the different mechanisms responsible for an impairment of coronary vasodilator capacity in hypertensive subjects by an integrated echocardiographic approach, including transesophageal Doppler echocardiography, which allows noninvasive monitoring of coronary flow velocity in the left anterior descending artery during pharmacological vasodilation. The study population consisted of 17 healthy control subjects and 33 hypertensive subjects: 10 without hypertrophy, 16 with mild to moderate hypertrophy, and 7 with severe left ventricular hypertrophy. Mean systolic and diastolic flow velocities were monitored basally (together with indexes of myocardial oxygen demand, such as heart rate, myocardial inotropism, and left ventricular wall stress) and during infusion of low-dose (0.56 mg/kg per 4 minutes) and high-dose (0.84 mg/kg per 9 minutes) dipyridamole. Coronary reserve was assessed as the ratio of mean diastolic velocity after high-dose dipyridamole and basal diastolic velocity, and minimum coronary resistance as the ratio of diastolic blood pressure and diastolic velocity after high-dose dipyridamole. Compared with the control group, in all hypertensive groups, coronary reserve was similarly decreased (3.54 +/- 0.84 versus 2.59 +/- 0.42, 2.29 +/- 0.46, and 2.43 +/- 0.71; P < .01) and minimum resistance increased (0.56 +/- 0.15 versus 0.75 +/- 0.31, 0.75 +/- 0.19, and 0.78 +/- 0.21 mm Hg.s-1.cm-1; P = NS). These results confirm that coronary reserve in hypertensive individuals is reduced even before the occurrence of left ventricular hypertrophy. The reduction in coronary reserve depends on both an increase in resting coronary flow and an impairment in maximal vasodilator capacity. An increase in resting flow is dependent on higher heart rate and wall stress in hypertensive subjects without ventricular hypertrophy and on increased myocardial mass in hypertensive subjects with hypertrophy. Hypertensive subjects with ventricular hypertrophy also demonstrated a significantly blunted response to low-dose dipyridamole.

Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography.

BACKGROUND: Myocardial blood flow (MBF) impairment has been documented in advanced dilated cardiomyopathy (DCM) in which hemodynamic factors, secondary to severe ventricular dysfunction, may limit myocardial perfusion. To assess whether MBF impairment in DCM may also be present independent of hemodynamic factors, the present study was designed to quantify myocardial perfusion in patients with mild disease without overt heart failure. METHODS AND RESULTS: Absolute regional MBF (milliliters per minute per gram) was measured by positron emission tomography and 13N-ammonia in resting conditions, during pacing-induced tachycardia, and after dipyridamole infusion (0.56 mg/kg over 4 minutes) in 22 DCM patients and in 13 healthy subjects. Patients were in New York Heart Association functional class I-II and showed depressed left ventricular (LV) ejection fraction by radionuclide angiography (35 +/- 8%; range, 21% to 48%), normal coronary angiography, and normal or moderately increased LV end-diastolic pressure (9.2 +/- 5.5 mm Hg; range, 2 to 20 mm Hg). There were no differences in arterial blood pressure, heart rate, and rate-pressure product between patients and control subjects in the three study conditions. Compared with control subjects, DCM patients had lower mean MBF at rest (0.80 +/- 0.25 versus 1.08 +/- 0.20 mL.min-1.g-1, P < .01), during atrial pacing tachycardia (1.21 +/- 0.59 versus 2.03 +/- 0.64 mL.min-1.g-1, P < .01), and after dipyridamole infusion (1.91 +/- 0.76 versus 3.78 +/- 0.86 mL.min-1.g-1, P < .01). LV MBF values were related to baseline LV end-diastolic pressure at rest (r = -.57, P < .01) and during pacing (r = -.67, P < .01) but not after dipyridamole infusion (r = .19, P = .40). Five patients had LV end-diastolic pressure > 12 mm Hg; in 4, myocardial perfusion was severely depressed both at baseline and in response to stress. CONCLUSIONS: In patients with DCM without overt heart failure, myocardial perfusion is impaired both at rest and in response to vasodilating stimuli. The abnormalities in vasodilating capability can be present despite normal hemodynamics; progression of the disease is associated with more depressed myocardial perfusion.