Myocardial oxygen supply and demand imbalance predicts mortality in older nursing home residents: The PARTAGE study.

BACKGROUND: A mismatch between myocardial oxygen supply and demand is the most common cause of ischemic myocardial injury in older persons. The subendocardial viability ratio (SEVR) can usefully estimate the degree of myocardial perfusion relative to left-ventricular workload. The aim of the present study was to evaluate the ability of SEVR to predict long-term mortality in the older population. Additionally, we aimed to identify the SEVR cutoff value best predicting total mortality. METHODS: This is a multicenter, longitudinal study involving a large population of individuals older than 80 years living in nursing homes. Patients with cancer, severe dementia, and very low level of autonomy were excluded from the study. Participants were monitored for 10 years. Adverse outcomes were recorded every 3 months from inclusion to the end of the study. SEVR reflects the balance between subendocardial oxygen supply and demand, and was estimated non-invasively by analyzing the carotid pressure waveform recorded by applanation arterial tonometry. RESULTS: A total of 828 people were enrolled (mean age: 87.7 ± 4.7 years, 78% female). 735 patients died within 10 years and 24 were lost to follow-up. SEVR was inversely associated with mortality at univariate Cox-regression model (risk ratio, 0.683 per unit increase in SEVR; 95% confidence interval (CI) [0.502-0.930], p = 0.015) and in a model including age, sex, body mass index, Activity of Daily Living index and Mini-Mental State Examination score (risk ratio, 0.647; 95% CI [0.472-0.930]). The lowest tertile of SEVR was associated with higher 10-years total mortality than the middle (p < 0.001) and the highest (p < 0.004) tertile. A SEVR cutoff value of 83% was identified as the best predictor of total mortality. CONCLUSIONS: SEVR may be considered as a marker of "cardiovascular frailty." An accurate non-invasive estimation of SEVR could be a useful and independent parameter to assess survival probability in very old adults. TRIAL REGISTRATION: NCT00901355, registered on ClinicalTrials.gov website.

Microcirculatory and Rheological Adaptive Mechanisms at High Altitude in European Lowlander Hikers and Nepalese Highlanders.

BACKGROUND: Physical activity at high-altitudes is increasingly widespread, both for tourist trekking and for the growing tendency to carry out sports and training activities at high-altitudes. Acute exposure to this hypobaric-hypoxic condition induces several complex adaptive mechanisms involving the cardiovascular, respiratory and endocrine systems. A lack of these adaptive mechanisms in microcirculation may cause the onset of symptoms of acute mountain sickness, a frequent disturbance after acute exposure at high altitudes. The aim of our study was to evaluate the microcirculatory adaptive mechanisms at different altitudes, from 1350 to 5050 m a.s.l., during a scientific expedition in the Himalayas. METHODS: The main haematological parameters, blood viscosity and erythrocyte deformability were assessed at different altitudes on eight European lowlanders and on a group of eleven Nepalese highlanders. The microcirculation network was evaluated in vivo by conjunctival and periungual biomicroscopy. RESULTS: Europeans showed a progressive and significant reduction of blood filterability and an increase of whole blood viscosity which correlate with the increase of altitude (p < 0.02). In the Nepalese highlanders, haemorheological changes were already present at their residence altitude, 3400 m a.s.l. (p < 0.001 vs. Europeans). With the increase in altitude, a massive interstitial oedema appeared in all participants, associated with erythrocyte aggregation phenomena and slowing of the flow rate in the microcirculation. CONCLUSIONS: High altitude causes important and significant microcirculatory adaptations. These changes in microcirculation induced by hypobaric-hypoxic conditions should be considered when planning training and physical activity at altitude.

Haemodynamic Adaptive Mechanisms at High Altitude: Comparison between European Lowlanders and Nepalese Highlanders.

Background: Exposure to high altitudes determines several adaptive mechanisms affecting in a complex way the whole cardiovascular, respiratory, endocrine systems because of the hypobaric hypoxic condition. The aim of our study was to evaluate the circulatory adaptive mechanisms at high altitudes, during a scientific expedition in the Himalayas. Methods: Arterial distensibility was assessed measuring carotid-radial and carotid-femoral pulse wave velocity. Tests were carried out at several altitudes, from 1350 to 5050 m above sea level, on 8 lowlander European researchers and 11 highlander Nepalese porters. Results: In Europeans, systolic blood pressure and pulse pressure increased slightly but significantly with altitude (p < 0.05 and p < 0.001, respectively). Norepinephrine showed a significant increase after the lowlanders had spent some time at high altitude (p < 0.001). With increasing altitude, a progressive increase in carotid-radial and carotid-femoral pulse wave velocity values was observed in lowlanders, showing a particularly significant increase (p < 0.001) after staying at high altitude (carotid-radial pulse wave velocity, median value (interquartile range) from 9.2 (7.9−10.0) to 11.2 (10.9−11.8) m/s and carotid-femoral pulse wave velocity from 8.5 (7.9−9.0) to 11.3 (10.9−11.8) m/s). At high altitudes (3400 and 5050 m above sea level), no significant differences were observed between highlanders and lowlanders in hemodynamic parameters (blood pressure, carotid-radial and carotid-femoral pulse wave velocity). Conclusions: The progressive arterial stiffening with altitude observed in European lowlanders could explain the increase in systolic and pulse pressure values observed at high altitudes in this ethnic group. Further studies are needed to evaluate the role of aortic stiffening in the pathogenesis of acute mountain sickness.

Postoperative and mid-term hemodynamic changes after replacement of the ascending aorta.

OBJECTIVES: To evaluate aortic distensibility and pulse waveform patterns associated with the ascending aortic aneurysm, and to analyze the postoperative and mid-term hemodynamic changes induced by prosthetic replacement of the ascending aorta. METHODS: Central blood pressure waves were recorded at the carotid artery level by means of a validated transcutaneous arterial tonometer in 30 patients undergoing prosthetic replacement of ascending aortic aneurysm and in 30 control patients. Measurements were obtained the day before surgery and 5 to 7 days and 16 to 20 months after surgery. RESULTS: The ascending aortic aneurysm was associated with a less steep slope of early systolic phase of the pressure curve (pulsus tardus) compared with a control group (0.54 ± 0.18 mm Hg/ms vs 0.69 ± 0.26 mm Hg/ms; P = .011). Replacing the ascending aorta with a noncompliant vascular prosthesis steepened the pulse pressure slope during the early systolic phase in the postoperative period (0.77 ± .29 mm Hg/ms), providing values comparable with those of the control group in the mid-term (0.67 ± .20 mm Hg/ms). No change in aortic stiffness was found either postoperatively or in the mid-term after ascending aorta surgical replacement (carotid-femoral pulse wave velocity: preoperative, 9.0 ± 2.6 m/s; postoperative, 9.0 ± 2.9 m/s; mid-term postoperative, 9.3 ± 2.8 m/s). CONCLUSIONS: This study does not confirm the assumption that substitution of the viscoelastic ascending aorta with a rigid prosthesis can cause serious hemodynamic alterations downstream, because we did not observe a worsening of global aortic distensibility after insertion of a rigid prosthetic aorta. The ascending aortic aneurysm is associated with a pulsus tardus.

Comparison Between Invasive and Noninvasive Methods to Estimate Subendocardial Oxygen Supply and Demand Imbalance.

Background Estimation of the balance between subendocardial oxygen supply and demand could be a useful parameter to assess the risk of myocardial ischemia. Evaluation of the subendocardial viability ratio (SEVR, also known as Buckberg index) by invasive recording of left ventricular and aortic pressure curves represents a valid method to estimate the degree of myocardial perfusion relative to left ventricular workload. However, routine clinical use of this parameter requires its noninvasive estimation and the demonstration of its reliability. Methods and Results Arterial applanation tonometry allows a noninvasive estimation of SEVR as the ratio of the areas directly beneath the central aortic pressure curves obtained during diastole (myocardial oxygen supply) and during systole (myocardial oxygen demand). However, this "traditional" method does not account for the intra-ventricular diastolic pressure and proper allocation to systole and diastole of left ventricular isometric contraction and relaxation, respectively, resulting in an overestimation of the SEVR values. These issues are considered in the novel method for SEVR assessment tested in this study. SEVR values estimated with carotid tonometry by "traditional" and "new" method were compared with those evaluated invasively by cardiac catheterization. The "traditional" method provided significantly higher SEVR values than the reference invasive SEVR: average of differences±SD= 44±11% (limits of agreement: 23% - 65%). The noninvasive "new" method showed a much better agreement with the invasive determination of SEVR: average of differences±SD= 0±8% (limits of agreement: -15% to 16%). Conclusions Carotid applanation tonometry provides valid noninvasive SEVR values only when all the main factors determining myocardial supply and demand flow are considered.

Mean arterial pressure estimated by brachial pulse wave analysis and comparison with currently used algorithms.

OBJECTIVE: Mean arterial pressure (MAP) is usually calculated by adding one-third of pulse pressure (PP) to DBP. This formula assumes that the average value of pulse waveform is constant in all individuals and coincides with 33.3% of PP amplitude (MAP = DBP + PP × 0.333). Other formulas were lately proposed to improve the MAP estimation, adding to DBP an established percentage of PP: MAP = DBP + PP × 0.40; MAP = DBP + PP × 0.412; MAP = DBP + PP × 0.333 + 5 mmHg. METHODS: The current study evaluated the integral of brachial pulse waveform recorded by applanation tonometry in 1526 patients belonging to three distinct cohorts: normotensive or hypertensive elderly, hypertensive adults, and normotensive adults. RESULTS: The percentage of PP to be added to DBP to obtain MAP was extremely variable among individuals, ranging from 23 to 58% (mean: 42.2 ±â€Š5.5%), higher in women (42.9 ±â€Š5.6%) than men (41.2 ±â€Š5.1%, P < 0.001), lower in the elderly cohort (40.9 ±â€Š5.3%) than in the general population cohort (42.8 ±â€Š6.0%, P < 0.001) and in the hypertensive patients (42.4 ±â€Š4.8%, P < 0.001). This percentage was significantly associated with DBP (ß = 0.357, P < 0.001) and sex (ß = 0.203, P < 0.001) and significantly increased after mental stress test in 19 healthy volunteers (from 39.9 ±â€Š3.2 at baseline, to 43.0 ±â€Š4.0, P < 0.0001). The average difference between MAP values estimated by formulas, compared with MAP assessed on the brachial tonometric curve, was (mean ±â€Š1.96 × SD): -5.0 ±â€Š6.7 mmHg when MAP = DBP + PP × 0333; -1.2 ±â€Š6.1 mmHg when MAP = DBP + PP × 0.40; -0.6 ±â€Š6.1 mmHg when MAP = DBP + PP × 0.412; -0.4 ±â€Š6.7 mmHg when MAP = DBP + PP × 0.333 + 5. CONCLUSION: Due to high interindividual and intraindividual variability of pulse waveform, the estimation of MAP based on fixed formulas derived from SBP and DBP is unreliable. Conversely, a more accurate estimation of MAP should be based on the pulse waveform analysis.

Sodium Intake and Hypertension.

The close relationship between hypertension and dietary sodium intake is widely recognized and supported by several studies. A reduction in dietary sodium not only decreases the blood pressure and the incidence of hypertension, but is also associated with a reduction in morbidity and mortality from cardiovascular diseases. Prolonged modest reduction in salt intake induces a relevant fall in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group, with larger falls in systolic blood pressure for larger reductions in dietary salt. The high sodium intake and the increase in blood pressure levels are related to water retention, increase in systemic peripheral resistance, alterations in the endothelial function, changes in the structure and function of large elastic arteries, modification in sympathetic activity, and in the autonomic neuronal modulation of the cardiovascular system. In this review, we have focused on the effects of sodium intake on vascular hemodynamics and their implication in the pathogenesis of hypertension.

Noninvasive Estimation of Aortic Stiffness Through Different Approaches.

Aortic pulse wave velocity is a worldwide accepted index to evaluate aortic stiffness and can be assessed noninvasively by several methods. This study sought to determine if commonly used noninvasive devices can all accurately estimate aortic pulse wave velocity. Pulse wave velocity was estimated in 102 patients (aged 65±13 years) undergoing diagnostic coronary angiography with 7 noninvasive devices and compared with invasive aortic pulse wave velocity. Devices evaluating carotid-femoral pulse wave velocity (Complior Analyse, PulsePen ET, PulsePen ETT, and SphygmoCor) showed a strong agreement between each other ( r>0.83) and with invasive aortic pulse wave velocity. The mean difference ±SD with the invasive pulse wave velocity was -0.73±2.83 m/s ( r=0.64) for Complior-Analyse: 0.20±2.54 m/s ( r=0.71) for PulsePen-ETT: -0.04±2.33 m/s ( r=0.78) for PulsePen ET; and -0.61±2.57 m/s ( r=0.70) for SphygmoCor. The finger-toe pulse wave velocity, evaluated by pOpmètre, showed only a weak relationship with invasive aortic recording (mean difference ±SD =-0.44±4.44 m/s; r=0.41), and with noninvasive carotid-femoral pulse wave velocity measurements ( r<0.33). Pulse wave velocity estimated through a proprietary algorithm by BPLab (v.5.03 and v.6.02) and Mobil-O-Graph showed a weaker agreement with invasive pulse wave velocity compared with carotid-femoral pulse wave velocity (mean difference ±SD =-0.71±3.55 m/s, r=0.23; 1.04±2.27 m/s, r=0.77; and -1.01±2.54 m/s, r=0.71, respectively), revealing a negative proportional bias at Bland-Altman plot. Aortic pulse wave velocity values provided by BPLab and Mobil-O-Graph were entirely dependent on age-squared and peripheral systolic blood pressure (cumulative r2=0.98 and 0.99, respectively). Thus, among the methods evaluated, only those assessing carotid-femoral pulse wave velocity (Complior Analyse, PulsePen ETT, PulsePen ET, and SphygmoCor) appear to be reliable approaches for estimation of aortic stiffness.

Unreliable Estimation of Aortic Pulse Wave Velocity Provided by the Mobil-O-Graph Algorithm-Based System in Marfan Syndrome.

Background Several devices have been proposed to assess arterial stiffness in clinical daily use over the past few years, by estimating aortic pulse wave velocity (PWV) from a single measurement of brachial oscillometric blood pressure, using patented algorithms. It is uncertain if these systems are able to provide additional elements, beyond the contribution carried by age and blood pressure levels, in the definition of early vascular damage expressed by the stiffening of the arterial wall. Methods and Results The aim of our study was to compare the estimated algorithm-based PWV values, provided by the Mobil-O-Graph system, with the standard noninvasive assessment of aortic PWV in patients with Marfan syndrome (ie, in subjects characterized by premature aortic stiffening and low blood pressure values). Aortic stiffness was simultaneously evaluated by carotid-femoral PWV with a validated arterial tonometer and estimated with an arm cuff-based ambulatory blood pressure monitoring Mobil-O-Graph device on 103 patients with Marfan syndrome (50 men; mean± SD age, 38±15 years). Aortic PWV, estimated by the Mobil-O-Graph, was significantly ( P<0.0001) lower (mean± SD, 6.1±1.3 m/s) than carotid-femoral PWV provided by arterial tonometry (mean± SD , 8.8±3.1 m/s). The average of differences between PWV values provided by the 2 methods (±1.96×SD) was -2.7±5.7 m/s. Conclusions The Mobil-O-Graph provides PWV values related to an ideal subject for a given age and blood pressure, but it is not able to evaluate early vascular aging expressed by high PWV in the individual patient. This is well shown in patients with Marfan syndrome.

Systolic time intervals assessed from analysis of the carotid pressure waveform.

OBJECTIVE: The timing of mechanical cardiac events is usually evaluated by conventional echocardiography as an index of cardiac systolic function and predictor of cardiovascular outcomes. We aimed to measure the systolic time intervals, namely the isovolumetric contraction time (ICT) and pre-ejection period (PEP), by arterial tonometry. APPROACH: Sixty-two healthy volunteers (age 47 ± 17 years) and 42 patients with heart failure and reduced ejection fraction were enrolled (age 66 ± 14 years). Pulse waves were recorded at the carotid artery by arterial tonometry together with simultaneous aortic transvalvular flow by Doppler-echocardiography, synchronized by electrocardiographic gating. The ICT was determined from the time delay between the electrical R wave and the carotid pressure waveform, after adjustment for the pulse transit time from the aortic valve to the carotid artery site, estimated by an algorithm based on the carotid-femoral pulse wave velocity. The PEP was evaluated by adding the electrical QR duration to the ICT. MAIN RESULTS: The ICT derived from carotid pulse wave analysis was closely related to that measured by echocardiography (r = 0.90, p < 0.0001), with homogeneous distribution in Bland-Altman analysis (mean difference and 95% confidence interval = 0.2 from -14.2 to 14.5 ms). ICT and PEP were higher in cardiac patients than in healthy volunteers (p < 0.0001). The ratio between PEP and left ventricular ejection time was related to the ejection fraction measured with echocardiography (r = 0.555, p < 0.0001). SIGNIFICANCE: The timing of electro-mechanical cardiac events can be reliably obtained from the carotid pulse waveform and carotid-femoral PWV, evaluated using arterial tonometry. Systolic time intervals assessed with this approach showed good agreement with measurements performed with conventional echocardiography and may represent a promising additional application of arterial tonometry.

Aortic dilatation in Marfan syndrome: role of arterial stiffness and fibrillin-1 variants.

OBJECTIVE: Marfan syndrome (MFS) is an autosomal dominant genetic disorder characterized by aortic root dilation and dissection and an abnormal fibrillin-1 synthesis. In this observational study, we evaluated aortic stiffness in MFS and its association with ascending aorta diameters and fibrillin-1 genotype. METHODS: A total of 116 Marfan adult patients without history of cardiovascular surgery, and 144 age, sex, blood pressure and heart rate matched controls were enrolled. All patients underwent arterial stiffness evaluation through carotid-femoral pulse wave velocity (PWV) and central blood pressure waveform analysis (PulsePen tonometer). Fibrillin-1 mutations were classified based on the effect on the protein, into 'dominant negative' and 'haploinsufficient' mutations. RESULTS: PWV and central pulse pressure were significantly higher in MFS patients than in controls [respectively 7.31 (6.81-7.44) vs. 6.69 (6.52-6.86) m/s, P = 0.0008; 41.3 (39.1-43.5) vs. 34.0 (32.7-35.3) mmHg, P < 0.0001], with a higher age-related increase of PWV in MFS (ß 0.062 vs. 0.036). Pressure amplification was significantly reduced in MFS [18.2 (15.9-20.5) vs. 33.4 (31.6-35.2)%, P < 0.0001]. Central pressure profile was altered even in MFS patients without aortic dilatation. Multiple linear regression models showed that PWV independently predicted aortic diameters at the sinuses of Valsalva (ß = 0.243, P = 0.002) and at the sinotubular junction (ß = 0.186, P = 0.048). PWV was higher in 'dominant negative' than 'haploinsufficient' fibrillin-1 mutations [7.37 (7.04-7.70) vs. 6.60 (5.97-7.23) m/s, P = 0.035], although this difference was not significant after adjustment. CONCLUSION: Aortic stiffness is increased in MFS, independently from fibrillin-1 genotype and is associated with diameters of ascending aorta. Alterations in central hemodynamics are present even when aortic diameter is within normal limits. Our findings suggest an accelerated arterial aging in MFS.

Impaired Central Pulsatile Hemodynamics in Children and Adolescents With Marfan Syndrome.

BACKGROUND: Marfan syndrome is characterized by aortic root dilation, beginning in childhood. Data about aortic pulsatile hemodynamics and stiffness in pediatric age are currently lacking. METHODS AND RESULTS: In 51 young patients with Marfan syndrome (12.0±3.3 years), carotid tonometry was performed for the measurement of central pulse pressure, pulse pressure amplification, and aortic stiffness (carotid-femoral pulse wave velocity). Patients underwent an echocardiogram at baseline and at 1 year follow-up and a genetic evaluation. Pathogenetic fibrillin-1 mutations were classified between "dominant negative" and "haploinsufficient." The hemodynamic parameters of patients were compared with those of 80 sex, age, blood pressure, and heart-rate matched controls. Central pulse pressure was significantly higher (38.3±12.3 versus 33.6±7.8 mm Hg; P=0.009), and pulse pressure amplification was significantly reduced in Marfan than controls (17.9±15.3% versus 32.3±17.4%; P<0.0001). Pulse wave velocity was not significantly different between Marfan and controls (4.98±1.00 versus 4.75±0.67 m/s). In the Marfan group, central pulse pressure and pulse pressure amplification were independently associated with aortic diameter at the sinuses of Valsalva (respectively, ß=0.371, P=0.010; ß=-0.271, P=0.026). No significant difference in hemodynamic parameters was found according to fibrillin-1 genotype. Patients who increased aortic Z-scores at 1-year follow-up presented a higher central pulse pressure than the remaining (42.7±14.2 versus 32.3±5.9 mm Hg; P=0.004). CONCLUSIONS: Central pulse pressure and pulse pressure amplification were impaired in pediatric Marfan syndrome, and associated with aortic root diameters, whereas aortic pulse wave velocity was similar to that of a general pediatric population. An increased central pulse pressure was present among patients whose aortic dilatation worsened at 1-year follow-up.

Short-Term Repeatability of Noninvasive Aortic Pulse Wave Velocity Assessment: Comparison Between Methods and Devices.

BACKGROUND: Aortic pulse wave velocity (PWV) is an indirect index of arterial stiffness and an independent cardiovascular risk factor. Consistency of PWV assessment over time is thus an essential feature for its clinical application. However, studies providing a comparative estimate of the reproducibility of PWV across different noninvasive devices are lacking, especially in the elderly and in individuals at high cardiovascular risk. METHODS: Aimed at filling this gap, short-term repeatability of PWV, estimated with 6 different devices (Complior Analyse, PulsePen-ETT, PulsePen-ET, SphygmoCor Px/Vx, BPLab, and Mobil-O-Graph), was evaluated in 102 high cardiovascular risk patients hospitalized for suspected coronary artery disease (72 males, 65 ± 13 years). PWV was measured in a single session twice, at 15-minute interval, and its reproducibility was assessed though coefficient of variation (CV), coefficient of repeatability, and intraclass correlation coefficient. RESULTS: The CV of PWV, measured with any of these devices, was <10%. Repeatability was higher with cuff-based methods (BPLab: CV = 5.5% and Mobil-O-Graph: CV = 3.4%) than with devices measuring carotid-femoral PWV (Complior: CV = 8.2%; PulsePen-TT: CV = 8.0%; PulsePen-ETT: CV = 5.8%; and SphygmoCor: CV = 9.5%). In the latter group, PWV repeatability was lower in subjects with higher carotid-femoral PWV. The differences in PWV between repeated measurements, except for the Mobil-O-Graph, did not depend on short-term variations of mean blood pressure or heart rate. CONCLUSIONS: Our study shows that the short-term repeatability of PWV measures is good but not homogenous across different devices and at different PWV values. These findings, obtained in patients at high cardiovascular risk, may be relevant when evaluating the prognostic importance of PWV.

Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?

BACKGROUND: Losartan is under evaluation for managing Marfan patients with aortic root dilatation. Cytochrome P450 (CYP) enzymes convert losartan to E3174 active metabolite. The aim of this study is to describe the distribution of CYP2C9*2, CYP2C9*3, CYP3A4*22 and CYP3A5*3 defective alleles, according to losartan tolerance in paediatric Marfan patients. METHODS: We genotyped 53 paediatric Marfan patients treated with losartan. The rate of aortic root dilatation was evaluated using the delta z-score variation. Differences in tolerated losartan daily doses with respect to CYP metabolic classes were assessed through the Kruskal-Wallis test. RESULTS: The losartan daily dose spans from 0.16 to 2.50 mg/kg (median 1.10 mg/kg). As we expect from the pharmacokinetics pathway, we observe highest tolerated dose in CYP2C9 poor metabolisers (median 1.50 mg/kg, interquartile range 1.08-1.67 mg/kg); however, this difference is not statistically significant. CONCLUSIONS: The optimal dose of angiotensin receptor blocker is not known, and no data are available about losartan pharmacogenetic profile in Marfan syndrome; we have proposed a strategy to tackle this issue based on evaluating the major genetic polymorphisms involved in the losartan conversion into active carboxylic acid metabolite. Further studies are needed to support the use of genetic polymorphisms as predictors of the right dose of losartan.