Evelien Hermeling

The dicrotic notch as alternative time-reference point to measure local pulse wave velocity in the carotid artery by means of ultrasonography.

Objectives Increased arterial stiffness is associated with cardiovascular disease. Its applicability in individual patient management, however, is limited due to lack of reliable methods. We developed a method to measure arterial stiffness by means of local pulse wave velocity (PWV), using multiple M-mode ultrasound and the dicrotic notch (PWVdn) rather than the systolic foot (PWVsf) as time-reference point. Methods Systolic foot and dicrotic notch were determined in 14 simultaneously recorded distension waveforms obtained in young and older participants (mean age 26 and 59 years). Linear regression was performed on echo-line position and time-reference point, resulting in a local PWV estimate, either PWVsf or PWVdn. Results PWVdn, at about mean arterial pressure, had a better intra-individual variability (0.6 m/s) than PWVsf (1.1 m/s). The expected difference in stiffness between the two age categories was identified by PWVdn (P < 0.0001), but not by PWVsf. Moreover, in contrast to PWVsf, PWVdn showed a significant correlation with relative distension (r2 = 0.56) and the local distensibility coefficient (r2 = 0.52). Conclusion PWVdn is a noninvasive and suitable measure of arterial stiffness: it has a good reproducibility, discriminates well between age groups, and correlates with local distensibility. PWVdn does not require additional assessment of distance or local pulse pressure. Furthermore, PWVdn is measured locally, at near-mean arterial pressure, thereby better reflecting the effective arterial stiffness, which determines the load the left ventricle is subjected to as it ejects blood.

Combined 18F-FDG PET-CT and DCE-MRI to Assess Inflammation and Microvascularization in Atherosclerotic Plaques

Background and Purpose— Hallmarks of vulnerable atherosclerotic plaques are inflammation that can be assessed with 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography, and increased neovascularization that can be evaluated by dynamic contrast–enhanced-MRI. It remains unclear whether these parameters are correlated or represent independent imaging parameters. This study determines whether there is a correlation between inflammation and neovascularization in atherosclerotic carotid plaques. Methods— A total of 58 patients with transient ischemic attack or minor stroke in the carotid territory and ipsilateral carotid artery stenosis of 30% to 69% were included. All patients underwent positron emission tomography/computed tomography and dynamic contrast–enhanced-MRI of the carotid plaque. 18Fluorine-fluorodeoxyglucose standard uptake values with target/background ratio were determined. Neovascularization was quantified by the mean (leakage) volume transfer constant Ktrans. Spearman rank correlation coefficients between target/background ratio and Ktrans were calculated. Results— Images suitable for further analysis were obtained in 49 patients. A weak but significant positive correlation between target/background ratio and mean Ktrans (Spearman &rgr;=0.30 [P=0.035]) and 75th percentile Ktrans (Spearman &rgr;=0.29 [P=0.041]) was found. Conclusions— There is a weak but significant positive correlation between inflammation on positron emission tomography/computed tomography and neovascularization as assessed with dynamic contrast–enhanced-MRI. Future studies should investigate which imaging modality has the highest predictive value for recurrent stroke, as these are not interchangeable. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00451529.

Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice

Background— Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B−/− mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B−/−). Methods and Results— Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B−/− mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B−/− compound mutant mice exhibited a similar contractile deficit. Smtn-B−/− arteries had a normal architecture and expressed normal levels of other smooth muscle cell–specific genes, including smooth muscle myosin heavy chain, &agr;-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B−/− arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B−/− mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B−/− mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. Conclusions— Collectively, our results identify smoothelins as key determinants of arterial smooth muscle contractility and cardiovascular performance. Studies on mutations in the Smtn gene or alterations in smoothelin levels in connection to hypertension in humans are warranted.

The change in arterial stiffness over the cardiac cycle rather than diastolic stiffness is independently associated with left ventricular mass index in healthy middle-aged individuals

Background: The current standard for arterial stiffness assessment, aortic pulse wave velocity (aPWV), is measured at diastolic pressure. Arterial stiffness, however, is pressure dependent. At the carotid artery level, the degree of this dependency can be quantified as the difference (&Dgr;PWV) between systolic and diastolic (cPWVd) carotid pulse wave velocity. Biomechanically, a greater &Dgr;PWV implies greater increases in left ventricular afterload with physical activity. Therefore, we hypothesized, that &Dgr;PWV is more strongly associated with left ventricular mass index (LVMI) than aPWV and cPWVd. Methods: In 1776 healthy individuals from the Asklepios cohort (age 35–55 years), &Dgr;PWV was obtained from combined carotid artery ultrasound and tonometry recordings. Multiple linear regression analysis was performed to investigate the associations of &Dgr;PWV, cPWVd and aPWV with LVMI, adjusting for age, sex, mean blood pressure (MBP), central pulse pressure, and other possible confounders. Results: &Dgr;PWV was 2.4 ± 1.2 m/s (mean ± SD), ranging from 0.8 m/s, indicating almost constant arterial stiffness over the cardiac cycle, to 4.4 m/s, reflecting substantial pressure dependency. &Dgr;PWV was significantly associated with LVMI (&bgr; of 2.46 g/m1.7 per m/s, P < 0.001), even after full adjustment (&bgr; of 0.56 g/m1.7 per m/s, P = 0.03). cPWVd and aPWV had clear crude associations with LVMI (P < 0.001), but lost significance after adjustment (&bgr; of −0.48 and −0.33 g/m1.7 per m/s, with P = 0.11 and 0.2, respectively). Conclusion: The change in arterial stiffness over the cardiac cycle, rather than diastolic stiffness, is independently associated with LVMI in healthy middle-aged individuals. Therefore, the pressure dependency of arterial stiffness should be considered in cardiovascular risk assessment.

Pressure-dependence of arterial stiffness: potential clinical implications.

Background: Arterial stiffness measures such as pulse wave velocity (PWV) have a known dependence on actual blood pressure, requiring consideration in cardiovascular risk assessment and management. Given the impact of ageing on arterial wall structure, the pressure-dependence of PWV may vary with age. Methods: Using a noninvasive model-based approach, combining carotid artery echo-tracking and tonometry waveforms, we obtained pressure-area curves in 23 hypertensive patients at baseline and after 3 months of antihypertensive treatment. We predicted the follow-up PWV decrease using modelled baseline curves and follow-up pressures. In addition, on the basis of these curves, we estimated PWV values for two age groups (mean ages 41 and 64 years) at predefined hypertensive (160/90 mmHg) and normotensive (120/80 mmHg) pressure ranges. Results: Follow-up measurements showed a near 1 m/s decrease in carotid PWV when compared with baseline, which fully agreed with our model-prediction given the roughly 10 mmHg decrease in diastolic pressure. The stiffness-blood pressure-age pattern was in close agreement with corresponding data from the ‘Reference Values for Arterial Stiffness’ study, linking the physical and empirical bases of our findings. Conclusion: Our study demonstrates that the innate pressure-dependence of arterial stiffness may have implications for the clinical use of arterial stiffness measurements, both in risk assessment and in treatment monitoring of individual patients. We propose a number of clinically feasible approaches to account for the blood pressure effect on PWV measurements.

Confluence of incident and reflected waves interferes with systolic foot detection of the carotid artery distension waveform

Objectives Local pulse wave velocity, a direct measure of arterial stiffness, can be measured using the systolic foot of the pressure waveform as the time reference point. The accuracy and precision of systolic foot identification, which may be disturbed by early wave reflections, heavily affects pulse wave transit time measurements. We investigated within subjects the existence of early wave reflections and their interference with systolic foot identification. Methods Fourteen ultrasound-derived distension waveforms, spaced over 16.4 mm, were simultaneously recorded in the CCA 3 cm proximal of the bifurcation of 12 young subjects. The second derivatives of the distension waveforms were calculated to identify the systolic foot and an inflection point preceding systolic peak distension. Pulse wave transit time was calculated as the time difference between the most proximal and most distal time-point, using either the systolic foot or the inflection point. The time to reflection (ΔTSF_IP) was defined as the time difference between the systolic foot and the inflection point. Results Both transit times (TTSF and TTIP) could be determined with good intrasubject precision: 0.7 and 1.4 ms, respectively. The systolic foot is running forward, TTSF = 3.1 ± 0.9 ms, whereas the inflection point appears to run backward, TTIP = −3.9 ± 1.4 ms. ΔTSF_IP was 44.3 ± 8.8 ms. Conclusion Despite the good intrasubject reproducibility, confluence of incident and reflected waves disturbs identification and discrimination of the systolic foot and the inflection point, resulting in biased estimates. Therefore both points are unsuitable for local pulse transit time measurements in the common carotid artery.

Modeling cardiac electromechanics and mechanoelectrical coupling in dyssynchronous and failing hearts : insight from adaptive computer models

Computer models have become more and more a research tool to obtain mechanistic insight in the effects of dyssynchrony and heart failure. Increasing computational power in combination with increasing amounts of experimental and clinical data enables the development of mathematical models that describe electrical and mechanical behavior of the heart. By combining models based on data at the molecular and cellular level with models that describe organ function, so-called multi-scale models are created that describe heart function at different length and time scales. In this review, we describe basic modules that can be identified in multi-scale models of cardiac electromechanics. These modules simulate ionic membrane currents, calcium handling, excitation–contraction coupling, action potential propagation, and cardiac mechanics and hemodynamics. In addition, we discuss adaptive modeling approaches that aim to address long-term effects of diseases and therapy on growth, changes in fiber orientation, ionic membrane currents, and calcium handling. Finally, we discuss the first developments in patient-specific modeling. While current models still have shortcomings, well-chosen applications show promising results on some ultimate goals: understanding mechanisms of dyssynchronous heart failure and tuning pacing strategy to a particular patient, even before starting the therapy.

Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT

It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca(2+) current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventricular stroke work and increased end-diastolic volume. During sustained LBBB, MEC reduced intraventricular dispersion of mechanical workload and repolarization. However, MEC-induced reduction in contractility in late-activated regions was larger than the contractility increase in early-activated regions, resulting in further decrease of stroke work and increase of end-diastolic volume. Upon the start of CRT, stroke work increased despite a wider dispersion of mechanical workload. During sustained CRT, MEC-induced reduction in dispersion of workload and repolarization coincided with a further reduction in end-diastolic volume. In conclusion, MEC may represent a useful framework for better understanding the long-term changes in cardiac electrophysiology and contraction following LBBB as well as CRT.

Local blood pressure rather than shear stress should be blamed for plaque rupture.

A recent article ([1][1]) published in the Journal corroborates the hypothesis that shear stress triggers fibrous cap rupture. In 20 patients with considerable lumen narrowing (maximum area reduction of 80 ± 7%), ulcerative plaque rupture preferentially occurred in areas with locally high wall

Vessel Wall and Adventitial DCE-MRI Parameters Demonstrate Similar Correlations With Carotid Plaque Microvasculature on Histology

To assess parameter agreement of volume transfer coefficient (Ktrans) between two vascular regions and to study the correlation with microvessel density on histology. The dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) parameter Ktrans is frequently used to study atherosclerotic plaque microvasculature. Ktrans has been reported using different descriptive statistics (mean, median, 75th percentile) either for the whole vessel wall or the adventitia in previous studies.