Stephanie Parragh

Noninvasive methods to assess pulse wave velocity: comparison with the invasive gold standard and relationship with organ damage.

Objectives: To compare noninvasive methods to assess pulse wave velocity (PWV) with the invasive gold standard in terms of absolute values, age-related changes, and relationship with subclinical organ damage. Methods: Invasive aortic PWV (aoPWVinv) was measured in 915 patients undergoing cardiac catheterization (mean age 61 years, range 27–87 years). Carotid–femoral PWV (cfPWV) was measured with tonometry, using subtracted distance (cfPWVsub), body height-based estimated distance (cfPWVbh), direct distance × 0.8 (cfPWVdir0.8), and caliper-based distance (cfPWVcalip) for travel distance calculation. Aortic PWV was estimated (aoPWVestim) from single-point radial waveforms, age, and SBP. Results: Invasive and noninvasive transit times were strikingly similar (median values 60.8 versus 61.7 ms). In the entire group, median value of aoPWVinv was 8.3 m/s, of cfPWVsub and cfPWVbh 8.1 m/s, and of aoPWVest 8.5 m/s. CfPWVsub overestimated aoPWVinv in younger patients by 0.7 m/s and underestimated aoPWVinv in older patients by 1.7 m/s, with good agreement from 50 to 70 years of age. AoPWVestim differed from aoPWVinv by no more than 0.4 m/s across all age groups. CfPWVdir0.8, measured in 632 patients, overestimated aoPWVinv by 1.7 m/s in younger patients, with good agreement in middle-aged and older patients. CfPWVcalip, measured in 336 patients, underestimated aoPWVinv in all ages. In 536 patients with preserved systolic function, aoPWVinv and aoPWVestim were superior to cfPWVs in predicting coronary atherosclerosis, renal function impairment, left atrial enlargement, and diastolic dysfunction. Conclusion: CfPWVsub, cfPWVdir0.8, and aoPWVestim are reasonable surrogates for aoPWVinv. AoPWVinv predicts subclinical organ damage better than cfPWVs, and as good as aoPWVestim.

Non-invasive wave reflection quantification in patients with reduced ejection fraction

The non-invasive quantification of arterial wave reflection is an increasingly important concept in cardiovascular research. It is commonly based on pulse wave analysis (PWA) of aortic pressure. Alternatively, wave separation analysis (WSA) considering both aortic pressure and flow waveforms can be applied. Necessary estimates of aortic flow can be measured by Doppler ultrasound or provided by mathematical models. However, this approach has not been investigated intensively up to now in subjects developing systolic heart failure characterized by highly reduced ejection fraction (EF). We used non-invasively generated aortic pressure waveforms and Doppler flow measurements to derive wave reflection parameters in 61 patients with highly reduced and 122 patients with normal EF. Additionally we compared these readings with estimates from three different flow models known from literature (triangular, averaged, Windkessel). After correction for confounding factors, all parameters of wave reflection (PWA and WSA) were comparable for patients with reduced and normal EF. Wave separations assessed with the Windkessel based model were similar to those derived from Doppler flow in both groups. The averaged waveform performed poorer in reduced than in normal EF, whereas triangular flow represented a better approximation for reduced EF. Overall, the non-invasive assessment of WSA parameters based on mathematical models compared to ultrasound seems feasible in patients with reduced EF.

Determinants and covariates of central pressures and wave reflections in systolic heart failure

BACKGROUND In general, higher blood pressure levels and increased central pulsatility are indicators for increased cardiovascular risk. However, in systolic heart failure (SHF), this relationship is reversed. Therefore, the aim of this work is to compare pulsatile hemodynamics between patients with SHF and controls and to clarify the relationships between measures of cardiac and arterial function in the two groups. METHODS We used parameters derived from angiography, echocardiography, as well as from pulse wave analysis (PWA) and wave separation analysis (WSA) based on non-invasively assessed pressure and flow waves to quantify cardiac function, aortic stiffness and arterial wave reflection in 61 patients with highly reduced (rEF) and 122 matched control-patients with normal ejection fraction (nEF). RESULTS Invasively measured pulse wave velocity was comparable between the groups (8.6/8.05 m/s rEF/nEF, P = 0.24), whereas all measures derived by PWA and WSA were significantly decreased (augmentation index: 18.1/24.8 rEF/nEF, P < 0.01; reflection magnitude: 56.3/62.1 rEF/nEF, P < 0.01). However, these differences could be explained by the shortened ejection duration (ED) in rEF (ED: 269/308 ms rEF/nEF, P < 0.01; AIx: 22.2/22.8 rEF/nEF, P = 0.7; RM: 59.3/60.6 rEF/nEF, P = 0.47 after adjustment for ED). Ventricular function was positively associated with central pulse pressures in SHF in contrast to no or even a slightly negative association in controls. CONCLUSIONS The results suggest that the decreased measures of pulsatile function may be caused by impaired systolic function and altered interplay of left ventricle and vascular system rather than by a real reduction of wave reflections or aortic stiffness in SHF.

Assessment of Model Based (Input) Impedance, Pulse Wave Velocity, and Wave Reflection in the Asklepios Cohort

Objectives Arterial stiffness and wave reflection parameters assessed from both invasive and non-invasive pressure and flow readings are used as surrogates for ventricular and vascular load. They have been reported to predict adverse cardiovascular events, but clinical assessment is laborious and may limit widespread use. This study aims to investigate measures of arterial stiffness and central hemodynamics provided by arterial tonometry alone and in combination with aortic root flows derived by echocardiography against surrogates derived by a mathematical pressure and flow model in a healthy middle-aged cohort. Methods Measurements of carotid artery tonometry and echocardiography were performed on 2226 ASKLEPIOS study participants and parameters of systemic hemodynamics, arterial stiffness and wave reflection based on pressure and flow were measured. In a second step, the analysis was repeated but echocardiography derived flows were substituted by flows provided by a novel mathematical model. This was followed by a quantitative method comparison. Results All investigated parameters showed a significant association between the methods. Overall agreement was acceptable for all parameters (mean differences: -0.0102 (0.033 SD) mmHg*s/ml for characteristic impedance, 0.36 (4.21 SD) mmHg for forward pressure amplitude, 2.26 (3.51 SD) mmHg for backward pressure amplitude and 0.717 (1.25 SD) m/s for pulse wave velocity). Conclusion The results indicate that the use of model-based surrogates in a healthy middle aged cohort is feasible and deserves further attention.

Wave intensity of aortic root pressure as diagnostic marker of left ventricular systolic dysfunction

Background Systolic left ventricular function strongly influences the blood pressure waveform. Therefore, pressure-derived parameters might potentially be used as non-invasive, diagnostic markers of left ventricular impairment. The aim of this study was to investigate the performance of pressure-based parameters in combination with electrocardiography (ECG) for the detection of left ventricular systolic dysfunction defined as severely reduced ejection fraction (EF). Methods and results Two populations, each comprising patients with reduced EF and pressure-matched controls, were included for the main analysis (51/102 patients) and model testing (44/88 patients). Central pressure was derived from radial readings and used to compute blood flow. Subsequently, pulse wave analysis and wave intensity analysis were performed and the ratio of the two peaks of forward intensity (SDR) was calculated as a novel index of ventricular function. SDR was significantly decreased in the reduced EF group (2.5 vs. 4.4, P<0.001), as was central pulse pressure, augmentation index and ejection duration (ED), while the QRS-duration was prolonged. SDR and ED were independent predictors of ventricular impairment and when combined with QRS in a simple decision tree, a reduced EF could be detected with a sensitivity of 92% and a specificity of 80%. The independent power of ED, SDR and QRS to predict reduced EF was furthermore confirmed in the test population. Conclusion The detection or indication of reduced ejection fraction from pressure-derived parameters seems feasible. These parameters could help to improve the quality of cardiovascular risk stratification or might be used in screening strategies in the general population.

[PP.19.11] COMPUTATIONAL ASSESSMENT OF MODEL BASED WAVE SEPARATION USING A DATABASE OF VIRTUAL SUBJECTS

Objective: An important area of interest in arterial pulse wave analysis is the quantification of arterial wave reflection. It can be achieved by wave separation analysis (WSA) if both the aortic pressure waveform and the aortic flow waveform are known. For better applicability, several mathematical models have been established to estimate aortic flow solely based on pressure waveforms. The aim of this study is to investigate and verify the model based wave separation of the ARCSolver method on virtual pulse wave measurements. Design and method: The study is based on a virtual database generated via simulations at the Kings College London. Seven cardiac and arterial parameters were varied within physiological healthy ranges, leading to a total of 3325 virtual healthy patients. Hemodynamic data is available at 11 locations within the arterial tree. For assessing the ARCSolver computationally, this method was used to perform WSA based on the aortic root pressure waveforms of the virtual patients. As a reference, the values of WSA using both the pressure waveforms and flow waveforms (scaled to 100 arbitrary units) provided by the virtual database were taken. For evaluating the performance of the modeling approach, the results of wave separation analysis using the mathematical model of the ARCSolver were compared against the reference. Results: The investigated parameters showed a good overall agreement between the model based method and the reference, see table. Mean differences and standard deviations were −0.05 ± 0.02 AU for characteristic impedance, −3.93 ± 1.79 mmHg for forward pressure amplitude, 1.37 ± 1.56 mmHg for backward pressure amplitude and 12.42 ± 4.88% for reflection magnitude. Conclusions: The results indicate that the mathematical flow model of the ARCSolver method is a feasible surrogate for a measured flow waveform and provides a reasonable way to assess arterial wave reflection non-invasively. Figure. No caption available.

Computational assessment of model-based wave separation using a database of virtual subjects

The quantification of arterial wave reflection is an important area of interest in arterial pulse wave analysis. It can be achieved by wave separation analysis (WSA) if both the aortic pressure waveform and the aortic flow waveform are known. For better applicability, several mathematical models have been established to estimate aortic flow solely based on pressure waveforms. The aim of this study is to investigate and verify the model-based wave separation of the ARCSolver method on virtual pulse wave measurements. The study is based on an open access virtual database generated via simulations. Seven cardiac and arterial parameters were varied within physiological healthy ranges, leading to a total of 3325 virtual healthy subjects. For assessing the model-based ARCSolver method computationally, this method was used to perform WSA based on the aortic root pressure waveforms of the virtual patients. Asa reference, the values of WSA using both the pressure and flow waveforms provided by the virtual database were taken. The investigated parameters showed a good overall agreement between the model-based method and the reference. Mean differences and standard deviations were -0.05±0.02AU for characteristic impedance, -3.93±1.79mmHg for forward pressure amplitude, 1.37±1.56mmHg for backward pressure amplitude and 12.42±4.88% for reflection magnitude. The results indicate that the mathematical blood flow model of the ARCSolver method is a feasible surrogate for a measured flow waveform and provides a reasonable way to assess arterial wave reflection non-invasively in healthy subjects.

[OP.1C.07] AORTIC PULSE WAVE VELOCITY PREDICTS SEVERE CARDIOVASCULAR EVENTS IN PATIENTS UNDERGOING CORONARY ANGIOGRAPHY.

Objective: Pulse wave velocity (PWV) predicts cardiovascular events in different patient groups and in the general population. Its value in patients evaluated for suspected coronary artery disease (CAD) has never been clarified. In addition, the particular value of “true” aortic PWV (aoPWV) is unknown. Design and method: We prospectively measured aoPWV invasively during catheter pullback in patients undergoing diagnostic coronary angiography (aoPWVmeas), and we estimated aoPWV non-invasively from age, systolic blood pressure, and waveform characteristics, using the validated ARCSolver method (aoPWVestim). The extent of CAD was expressed by an angiographic score, comprising number of diseased vessels and stenosis grade. Primary endpoint was a combination of death, myocardial infarction, stroke, and unplanned coronary revascularization. Follow-up information was obtained from general practitioners, hospital records, and our national registry of death. Multivariable Cox models included age, gender, systolic and diastolic function, extent of CAD, mean or diastolic blood pressure, presence of diabetes, smoking, and creatinine. Results: We included 1095 patients (mean age 62.6 years, 34.7% women, 75.3% hypertensives, 20.4% diabetics, 16.4% smokers). 47.5% were diagnosed with CAD, mean angioscore was 2.2. 12.7% had impaired systolic function. During a mean follow-up duration of 4.7 years, 267 patients suffered from one of the components of the primary endpoint (134 deaths, 45 myocardial infarctions, 42 strokes, 108 revascularizations). In univariate analysis, an increase of 1 m/sec of aoPWV was associated with a 13% (aoPWVinv) and 16.7% (aoPWVestim) higher risk of the primary endpoint. In Cox proportional hazards models, invasively determined aoPWVmeas (p = 0.04) as well as non-invasively estimated aoPWVestim (p = 0.01) remained significantly associated with the primary endpoint. The other significant predictors were male gender, extent of CAD, diastolic function, diabetes and smoking, whereas mean or diastolic blood pressure showed an inverse relationship. Conclusions: Aortic stiffness, both measured invasively or estimated non-invasively, is an independent prognostic marker in patients with suspected CAD.

[PP.11.01] AORTIC PULSE WAVE VELOCITY IS RELATED TO CORONARY HEART DISEASE IN WOMEN BUT NOT IN MEN

Objective Moderate age-dependent differences in aortic pulse wave velocity (PWV) between females and males have been reported previously. Nevertheless, studies on gender-specific interactions of PWV and cardiovascular diseases are lacking. Therefore, the aim of this study is to investigate age-dependent sex differences in PWV in relation to coronary heart disease (CHD). Design and method: A total of 645 patients from 60 to 79 years with suspected CHD underwent coronary angiography at the hospital in Wels-Grieskirchen (Austria). Invasive aortic PWV was measured in all patients by catheter pullback. According to the indication of the angiography, patients were divided into four groups (male/female, CHD/noCHD). As PWV strongly depends on age, patients were divided in two decades of life for further statistical analysis (60–69 years, 70–79 years). For both sexes, groups with and without CHD were compared. To minimize the influence of blood pressure, in a second step PWV was corrected for invasive aortic systolic blood pressure (aoSBP) by linear regression. Results: For each decade and each group, values of aoSBP, PWV and corrected PWV (corrPWV) can be found in the table. In both decades, differences in PWV between CHD and noCHD were not significant in males (p > 0.1), whereas differences were significant in females (p < 0.01). While aoSBP was significantly higher for patients with CHD in both sexes in decade 60–69 (p < 0.05), no significant differences could be found for patients aged 70–79 (p > 0.1). After accounting for unequal pressure levels, for females the differences in corrPWV between CHD and noCHD were still significant (p < 0.05), while they remained not statistically significant for males (p > 0.1). Conclusions: In patients with suspected coronary heart disease, pulse wave velocity is related to CHD in women but not in men. Blood pressure differences could not explain these results, as the effects remained when PWV was corrected for aortic systolic blood pressure. This finding indicates that a sex-dependent interplay between arterial stiffness and CHD is present which needs future attention. Figure. No caption available.

Is Blood Pressure Independent Arterial Destiffening Possible

Aging is associated with a stiffening of the large conduit arteries, which is accelerated by different cardiovascular risk factors, in particular by hypertension. Elevated aortic stiffness has therefore been included in the list of target organ damages to be screened for in hypertension by the European Society of Hypertension.1 Carotid-femoral pulse wave velocity (cfPWV) is the noninvasive “gold-standard” for the assessment of aortic stiffness2 and has been shown to be a powerful predictor of all-cause and cardiovascular mortality as well as cardiovascular events independent of classic cardiovascular risk factors.3 However, cfPWV has not yet fully qualified as surrogate endpoint,4 since its clinical use as therapeutic target still has to be demonstrated.5 Furthermore, a consensus on which strategy to pursue to selectively improve cfPWV is missing.6 In this context, the question if and how antihypertensive agents cause an arterial destiffening beyond the effect of blood pressure (BP) lowering alone has been receiving much attention.7–9 In this issue of the journal, Rodilla et al.10 present their results regarding the effect of antihypertensive treatment according to standard clinical practice on target organ damage with a special focus on arterial stiffness. In a population comprising 231 never-treated, mild hypertensives, and 125 controls, they measured BP, left ventricular mass index, urinary albumin excretion, and cfPWV at baseline and after 1 year to assess their changes with treatment. At follow up, BP levels were well-controlled and a significant reduction of left ventricular mass index and cfPWV could be observed. Age, gender, cfPWV at baseline, and change in BP were the main determinants of decrease in cfPWV. Rodilla et al. moreover found that all classes of antihypertensive drugs administered in the study, i.e., calcium channel blockers, angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (ACEI), vasodilating betablockers, and diuretics resulted in a significant lowering of adjusted cfPWV. It should be noted that diuretics were used as add-on agent in all but 2 patients. However, control subjects showed a similar reduction as hypertensive patients in mean blood pressure-adjusted cfPWV after 1 year and an effect of the antihypertensive treatment beyond BP could therefore not be clearly established. The main strength of the work by Rodilla et al.10 is the observational nature of their study, reflecting clinical routine rather than experimental design and highly selected patients. They were able to demonstrate that the prevalence of elevated arterial stiffness could be markedly decreased within a year by standard care in this relatively large group of mild hypertensives. Moreover, the study was conducted in accordance with the latest guidelines for the assessment of the target organ damages considered, including a cut-off value of 10 m/s to define elevated stiffness and the use of 0.8 times the direct carotid-tofemoral distance for the computation of cfPWV as advised in the expert consensus document on the measurement of aortic stiffness.2 Unfortunately though, cfPWV was only linearly adjusted for mean blood pressure using a regression equation obtained at baseline, whereby the reported interaction with age11 was not taken into account. Because hypertensive patients were significantly older than controls, this might have led to an underand over-adjustment of cfPWV respectively, making the results less comparable between the groups as well as between baseline and follow up in the treatment arm. A multiple regression approach including age as predictor, as chosen by Ong et al.12 or used by the reference values for arterial stiffness’ collaboration,11 might have been preferable to account for the strong association between BP, cfPWV, and age and might have eventually resulted in a more distinctly observable decrease in arterial stiffness with treatment. The stiffness of an artery represents a local, physical property of the vessel wall, and characterizes the relation between inner pressure and the induced distension of the vessel. This relation is nonlinear, meaning that arteries become stiffer as they dilate, which can be explained by the interplay between elastin and collagen fibers in the vessel media.6,13 Thus, higher BP results in a stiffer artery and, therefore, higher pulse wave velocity, yet without any change in the properties of the arterial wall itself. Arterial stiffening, in contrast, describes structural changes, which indeed affect the intrinsic properties of the vessel wall. For the same pressure level, a smaller distension and a higher pulse wave velocity will be observed in a stiffer artery compared to a more elastic one, implying that PWV is elevated beyond the effect of BP.