Relative contributions from the ventricle and arterial tree to arterial pressure and its amplification: an experimental study.

Arterial pressure is an important diagnostic parameter for cardiovascular disease. However, relative contributions of individual ventricular and arterial parameters in generating and augmenting pressure are not understood. Using a novel experimental arterial model, our aim was to characterize individual parameter contributions to arterial pressure and its amplification. A piston-driven ventricle provided programmable stroke profiles into various silicone arterial trees and a bovine aorta. Inotropy was varied in the ventricle, and arterial parameters modulated included wall thickness, taper and diameter, the presence of bifurcation, and a native aorta (bovine) versus silicone. Wave reflection at bifurcations was measured and compared with theory, varying parent-to-child tube diameter ratios, and branch angles. Intravascular pressure-tip wires and ultrasonic flow probes measured pressure and flow. Increasing ventricular inotropy independently augmented pressure amplification from 17% to 61% between the lower and higher systolic gradient stroke profiles in the silicone arterial network and from 10% to 32% in the bovine aorta. Amplification increased with presence of a bifurcation, decreasing wall thickness and vessel taper. Pulse pressure increased with increasing wall thickness (stiffness) and taper angle and decreasing diameter. Theoretical predictions of wave transmission through bifurcations werre similar to measurements (correlation: 0.91, R2 = 0.94) but underestimated wave reflection (correlation: 0.75, R2 = 0.94), indicating energy losses during mechanical wave reflection. This study offers the first comprehensive investigation of contributors to hypertensive pressure and its propagation throughout the arterial tree. Importantly, ventricular inotropy plays a crucial role in the amplification of peripheral pressure wave, which offers opportunity for noninvasive assessment of ventricular health.NEW & NOTEWORTHY The present study distinguishes contributions from cardiac and arterial parameters to elevated blood pressure and pressure amplification. Most importantly, it offers the first evidence that ventricular inotropy, an indicator of ventricular function, is an independent determinant of pressure amplification and could be measured with such established devices such as the SphygmoCor.

Three-dimensional atrial wall thickness maps to inform catheter ablation procedures for atrial fibrillation.

AIMS: Transmural lesion formation is critical to success in atrial fibrillation ablation and is dependent on left atrial wall thickness (LAWT). Pre- and peri-procedural planning may benefit from LAWT measurements. METHODS AND RESULTS: To calculate the LAWT, the Laplace equation was solved over a finite element mesh of the left atrium derived from the segmented computed tomographic angiography (CTA) dataset. Local LAWT was then calculated from the length of field lines derived from the Laplace solution that spanned the wall from the endocardium or epicardium. The method was validated on an atrium phantom and retrospectively applied to 10 patients who underwent routine coronary CTA for standard clinical indications at our institute. The Laplace wall thickness algorithm was validated on the left atrium phantom. Wall thickness measurements had errors of <0.2 mm for thicknesses of 0.5-5.0 mm that are attributed to image resolution and segmentation artefacts. Left atrial wall thickness measurements were performed on 10 patients. Successful comprehensive LAWT maps were generated in all patients from the coronary CTA images. Mean LAWT measurements ranged from 0.6 to 1.0 mm and showed significant inter and intra patient variability. CONCLUSIONS: Left atrial wall thickness can be measured robustly and efficiently across the whole left atrium using a solution of the Laplace equation over a finite element mesh of the left atrium. Further studies are indicated to determine whether the integration of LAWT maps into pre-existing 3D anatomical mapping systems may provide important anatomical information for guiding radiofrequency ablation.

Hemodynamic response to exercise and head-up tilt of patients implanted with a rotary blood pump: a computational modeling study.

The present study investigates the response of implantable rotary blood pump (IRBP)-assisted patients to exercise and head-up tilt (HUT), as well as the effect of alterations in the model parameter values on this response, using validated numerical models. Furthermore, we comparatively evaluate the performance of a number of previously proposed physiologically responsive controllers, including constant speed, constant flow pulsatility index (PI), constant average pressure difference between the aorta and the left atrium, constant average differential pump pressure, constant ratio between mean pump flow and pump flow pulsatility (ratioP I or linear Starling-like control), as well as constant left atrial pressure ( P l a ¯ ) control, with regard to their ability to increase cardiac output during exercise while maintaining circulatory stability upon HUT. Although native cardiac output increases automatically during exercise, increasing pump speed was able to further improve total cardiac output and reduce elevated filling pressures. At the same time, reduced venous return associated with upright posture was not shown to induce left ventricular (LV) suction. Although P l a ¯ control outperformed other control modes in its ability to increase cardiac output during exercise, it caused a fall in the mean arterial pressure upon HUT, which may cause postural hypotension or patient discomfort. To the contrary, maintaining constant average pressure difference between the aorta and the left atrium demonstrated superior performance in both exercise and HUT scenarios. Due to their strong dependence on the pump operating point, PI and ratioPI control performed poorly during exercise and HUT. Our simulation results also highlighted the importance of the baroreflex mechanism in determining the response of the IRBP-assisted patients to exercise and postural changes, where desensitized reflex response attenuated the percentage increase in cardiac output during exercise and substantially reduced the arterial pressure upon HUT.

Beat-to-beat variation in pulse wave velocity during breathing maneuvers.

PURPOSE: Thoracic pulse wave velocity (PWV) variation due to modulated trans-mural pressure (TMP) may indicate mechanical properties of the aorta. Our aim was to measure beat-to-beat thoracic PWV and TMP to observe its normal variation during respiratory maneuvers. METHODS: We validated PWV measurements from a real-time velocity projection MRI scan in a pulsatile phantom. A volunteer study showed inter-scan repeatability of steady-state PWV, and observed PWV variation when performing Mueller and Valsalva maneuvers. Synchronized to the real-time projection velocity data, TMP was measured using a mouth piece and pressure sensor arrangement monitoring the intra-thoracic pressure and a single arterial pressure measurement. RESULTS: In the phantom, beat-to-beat PWV derived from real-time projection (5.33 ± 0.32 m s(-1) ) agreed well with experimentally derived PWV using ultrasound probes (5.72 ± 0.50 m s(-1) ). The within-subject PWV variation between scans was 0.28 m s(-1) . Volunteers' PWVs increased during Mueller maneuver (TMP increase of 14.67 ± 10.69 mmHg) by 32% (P < 0.001), and during Valsalva maneuver (TMP decrease of TMP = 17.01 ± 12.91 mmHg), PWV response were inconsistent with an average increase of 14% (P < 0.05). CONCLUSION: Gating TMP to beat-to-beat PWV allows insight into how aortic stiffness varies with strain. However, quantifying nonlinear arterial stiffness requires real-time arterial pressure measurement.

Starling-like flow control of a left ventricular assist device: in vitro validation.

The application of rotary left ventricular (LV) assist devices (LVADs) is expanding from bridge to transplant, to destination and bridge to recovery therapy. Conventional constant speed LVAD controllers do not regulate flow according to preload, and can cause over/underpumping, leading to harmful ventricular suction or pulmonary edema, respectively. We implemented a novel adaptive controller which maintains a linear relationship between mean flow and flow pulsatility to imitate native Starling-like flow regulation which requires only the measurement of VAD flow. In vitro controller evaluation was conducted and the flow sensitivity was compared during simulations of postural change, pulmonary hypertension, and the transition from sleep to wake. The Starling-like controller's flow sensitivity to preload was measured as 0.39 L/min/mm Hg, 10 times greater than constant speed control (0.04 L/min/mm Hg). Constant speed control induced LV suction after sudden simulated pulmonary hypertension, whereas Starling-like control reduced mean flow from 4.14 to 3.58 L/min, maintaining safe support. From simulated sleep to wake, Starling-like control increased flow 2.93 to 4.11 L/min as a response to the increased residual LV pulsatility. The proposed controller has the potential to better match device outflow to patient demand in comparison with conventional constant speed control.

Increasing the transmitted flow pulse in a rotary left ventricular assist device.

Long-term rotary left ventricular assist devices (LVADs) are increasingly employed to bridge patients with end-stage heart failure to transplant or as a destination therapy. Significant recent device development has increased patient support times, shifting further development focus toward physiologically sensitive control of the pump operation. Sensorless control of these devices would benefit from increased observability of the ventricular volume/preload to the pump, in order to regulate flow based on preload, imitating the native Frank-Starling flow control. Monitoring the transmitted flow pulse through the pump has been used as a surrogate for preload, although means of maximizing its transmission are not clear. However, it is known that a flat hydraulic performance curve of the rotary pump induces high changes in flow for a given change in pressure head. The aim of this study was to determine geometric pump parameters responsible for increasing this flow pulse transmission and to demonstrate this increase in vitro. The sensitivity of the performance gradient to blade angles, blade heights, blade clearance, and channel areas were studied. Resulting pressure head, flow, and hydraulic efficiency were analyzed with respect to textbook designed procedures. Then pumps with comparably "flat" and "steep" performance curves were used to simulate LVAD support in vitro over a range of pump flow rates to observe the transmitted flow pulsatility. It was found that an outlet blade angle of 90°, inlet blade angle between 25 and 45°, and large throat area generated a "flatter" performance curve. The transmitted flow pulsatility through a pump with a flat performance curve was 68% higher than that of a steep performance curve at a flow rate of 5 L/min. Substantial gains in the observability of LVAD preload/resident blood volume in the ventricle exist through the careful selection of specific pump geometries.

Comparison of preload-sensitive pressure and flow controller strategies for a dual device biventricular support system.

The use of rotary left ventricular assist devices (LVADs) has extended to destination and recovery therapy for end-stage heart failure. Incidence of right ventricular failure while on LVAD support requires a second device be implanted to support the failing right ventricle. Without a commercially available implantable rotary right ventricular assist device, rotary LVADs are cannulated into the right heart and operation modified to provide suitable support for the pulmonary system. While this approach can alleviate the demand for transplant through long-term biventricular support, it uncovers a new challenge with respect to controller strategies for these dual device support systems. This study compares the preload sensitivity of rotary, dual device biventricular assistance controllers in light of their ability to adjust the flow rate according to physiological demand. A Frank-Starling-like flow controller which requires both inlet pressure and flow sensors is compared to pressure controllers which maintain atrial or inlet cannula pressures through the use of a single pressure sensor. It was found that cannula selection and the location of a pressure controller's single pressure sensor can be tailored to adjust the preload sensitivity. When located within the atria, this sensitivity is effectively infinite. Moving the sensor to the base of a 450-mm cannula, however, decreased the sensitivity to 0.22 (L/min)/mm Hg. This indicates the potential for simple and reliable VAD controllers with increased preload sensitivity without the need for complex controllers requiring an array of hemodynamic sensors.

Theoretical foundations of a Starling-like controller for rotary blood pumps.

A clinically intuitive physiologic controller is desired to improve the interaction between implantable rotary blood pumps and the cardiovascular system. This controller should restore the Starling mechanism of the heart, thus preventing overpumping and underpumping scenarios plaguing their implementation. A linear Starling-like controller for pump flow which emulated the response of the natural left ventricle (LV) to changes in preload was then derived using pump flow pulsatility as the feedback variable. The controller could also adapt the control line gradient to accommodate longer-term changes in cardiovascular parameters, most importantly LV contractility which caused flow pulsatility to move outside predefined limits. To justify the choice of flow pulsatility, four different pulsatility measures (pump flow, speed, current, and pump head pressure) were investigated as possible surrogates for LV stroke work. Simulations using a validated numerical model were used to examine the relationships between LV stroke work and these measures. All were approximately linear (r(2) (mean ± SD) = 0.989 ± 0.013, n = 30) between the limits of ventricular suction and opening of the aortic valve. After aortic valve opening, the four measures differed greatly in sensitivity to further increases in LV stroke work. Pump flow pulsatility showed more correspondence with changes in LV stroke work before and after opening of the aortic valve and was least affected by changes in the LV and right ventricular (RV) contractility, blood volume, peripheral vascular resistance, and heart rate. The system (flow pulsatility) response to primary changes in pump flow was then demonstrated to be appropriate for stable control of the circulation. As medical practitioners have an instinctive understanding of the Starling curve, which is central to the synchronization of LV and RV outputs, the intuitiveness of the proposed Starling-like controller will promote acceptance and enable rational integration into patterns of hemodynamic management.

Assessment of right pump outflow banding and speed changes on pulmonary hemodynamics during biventricular support with two rotary left ventricular assist devices.

The absence of an effective, easily implantable right ventricular assist device (RVAD) significantly diminishes long-term treatment options for patients with biventricular heart failure. The implantation of a second rotary left ventricular assist device (LVAD) for right heart support is therefore being considered; however, this approach exhibits technical challenges when adapting current devices to produce the lower pressures required of the pulmonary circulation. Hemodynamic adaptation may be achieved by either reducing the rotational speed of the right pump impeller or reducing the diameter of the right outflow cannula by the placement of a restricting band; however, the optimal value and influence of changes to each parameter are not well understood. Hemodynamics were therefore investigated using different banding diameters of the right outflow cannula (3-6.5 mm) and pump speeds (500-4500 rpm), using two identical rotary blood pumps coupled to a pulsatile mock circulation loop. Reducing the speed of the right pump from 4900 rpm (for left ventricle support) to 3500 rpm, or banding the Ø10 mm (area 78.5 mm²) right outflow graft to Ø5.4 mm (22.9 mm²) produced suitable hemodynamics. Pulmonary pressures were most sensitive to banding diameters, especially when RVAD flow exceeded LVAD flow. This occurred between Ø5.3 and Ø6.5 mm (22.05-38.5 mm²) and speeds between 3200 and 4400 rpm, with the flow imbalance potentially leading to pulmonary congestion. Total flow was not affected by banding diameters and speeds below this range, and only increased slightly at higher values. Both right outflow banding or right pump speed reduction were found to be effective techniques to allow a rotary LVAD to be used directly for right heart support. However, the observed sensitivity to diameter and speed indicate that challenges may be presented when setting appropriate values for each patient, and control over these parameters is desirable.

In vitro evaluation of a compliant inflow cannula reservoir to reduce suction events with extracorporeal rotary ventricular assist device support.

Limited preload sensitivity of rotary left ventricular assist devices (LVADs) renders patients susceptible to harmful atrial or ventricular suction events. Active control systems may be used to rectify this problem; however, they usually depend on unreliable sensors or potentially inaccurate inferred data from, for example, motor current. This study aimed to characterize the performance of a collapsible inflow cannula reservoir as a passive control system to eliminate suction events in extracorporeal, rotary LVAD support. The reservoir was evaluated in a mock circulation loop against a rigid cannula under conditions of reduced preload and increased LVAD speed in both atrial and ventricular cannulation scenarios. Both cases demonstrated the ease with which chamber suction events can occur with a rigid cannula and confirm that the addition of the reservoir maintained positive chamber volumes with reduced preload and high LVAD speeds. Reservoir performance was dependent on height with respect to the cannulated chamber, with lower placement required in atrial cannulation due to reduced filling pressures. This study concluded that a collapsible inflow cannula is capable of minimizing suction events in extracorporeal, rotary LVAD support.

A passively controlled biventricular support device.

Clinical studies have reported the balancing of pump outputs to be a serious control issue for rotary biventricular support (BiVS) systems. Poor reliability of long-term, blood immersed pressure sensors encouraged the development of a new control strategy to improve their viability. A rotary BiVS device was designed and constructed with a mechanical passive controller to autoregulate pump outputs to emulate the native baroreceptor response. In vitro testing in a dual circuit, hydraulic mock circulation loop showed that the prototype was able to maintain arterial pressures when subjected to sudden induced hemodynamic destabilization. However, inlet suction was observed when sudden simulated hypertension briefly reduced venous return to the cannulated ventricle. The results have encouraged further development of the device as a means to create an inherently stable, fully passive biventricular support device.

Optimizing the response from a passively controlled biventricular assist device.

Recent studies into rotary biventricular support have indicated that inadequate left/right flow balancing may lead to vascular congestion and/or ventricular suckdown. The implementation of a passive controller that automatically adjusts left/right flow during total and partial cardiac support would improve physiological interaction. This has encouraged the development of a biventricular assist device (BiVAD) prototype that achieves passive control of the two rotary pumps' hydraulic output by way of a nonrotating double pressure plate configuration, the hub, suspended between the ventricular assist device (VAD) impellers. Fluctuations in either the VAD's inlet or outlet pressure will cause the hub to translate, and in doing so, affect each pump's hydraulic outputs. In order to achieve partial support, the floating assembly needed to respond to pathologic blood pressure signals while being insensitive to residual ventricular function. An incorporated mechanical spring-mass-damper assembly affects the passive response to optimize the dynamic interaction between the prototype and the supported cardiovascular system. It was found that increasing the damping from a medium to a high level was effective in filtering out the higher frequency ventricular pressure signals, reducing a modified amplitude ratio by up to 72%. A spring response was also identified as being inherent in the passive response and was characterized as being highly nonlinear at the extremes of the floating assembly's translation range. The results from this study introduce a new means of BiVAD control as well as the characterization of a fully passive mechanical physiological controller.

Optimal Application of Fractional Flow Reserve to Assess Serial Coronary Artery Disease: A 3D-Printed Experimental Study With Clinical Validation.

Background Assessing the physiological significance of stenoses with coexistent serial disease is prone to error. We aimed to use 3-dimensional-printing to characterize serial stenosis interplay and to derive and validate a mathematical solution to predict true stenosis significance in serial disease. Methods and Results Fifty-two 3-dimensional-printed serial disease phantoms were physiologically assessed by pressure-wire pullback (Δ FFR app) and compared with phantoms with the stenosis in isolation (Δ FFR true). Mathematical models to minimize error in predicting FFR true, the FFR in the vessel where the stenosis is present in isolation, were subsequently developed using 32 phantoms and validated in another 20 and also a clinical cohort of 30 patients with serial disease. Δ FFR app underestimated Δ FFR true in 88% of phantoms, with underestimation proportional to total FFR . Discrepancy as a proportion of Δ FFR true was 17.1% (absolute difference 0.036±0.048), which improved to 2.9% (0.006±0.023) using our model. In the clinical cohort, discrepancy was 38.5% (0.05±0.04) with 13.3% of stenoses misclassified (using FFR <0.8 threshold). Using mathematical correction, this improved to 15.4% (0.02±0.03), with the proportion of misclassified stenoses falling to 6.7%. Conclusions Individual stenoses are considerably underestimated in serial disease, proportional to total FFR . We have shown within in vitro and clinical cohorts that this error is significantly improved using a mathematical correction model, incorporating routinely available pressure-wire pullback data.

Altered dependence of aortic pulse wave velocity on transmural pressure in hypertension revealing structural change in the aortic wall.

Aortic pulse wave velocity (aPWV), a major prognostic indicator of cardiovascular events, may be augmented in hypertension as a result of the aorta being stretched by a higher distending blood pressure or by a structural change. We used a novel technique to modulate intrathoracic pressure and thus aortic transmural pressure (TMP) to examine the variation of intrathoracic aPWV with TMP in hypertensive (n=20; mean±SD age, 52.1±15.3 years; blood pressure, 159.6±21.2/92.0±15.9 mm Hg) and normotensive (n=20; age, 55.5±11.1 years; blood pressure, 124.5±11.9/72.6±9.1 mm Hg) subjects. aPWV was measured using dual Doppler probes to insonate the right brachiocephalic artery and aorta at the level of the diaphragm. Resting aPWV was greater in hypertensive compared with normotensive subjects (897±50 cm/s versus 784±43 cm/s; P<0.05). aPWV was equal in hypertensive and normotensive subjects when measured at a TMP of 96 mm Hg. However, dependence of aPWV on TMP in normotensive subjects was greater than that in hypertensive subjects (9.6±1.6 versus 3.8±0.7 cm/s per mm Hg increase in TMP, respectively, means±SEM; P<0.01). This experimental behavior was best explained by a theoretical model incorporating strain-induced recruitment of stiffer fibers in normotensive subjects and fully recruited stiffer fibers in hypertensive subjects. These results explain previous contradictory findings with respect to isobaric aPWV in hypertensive compared with normotensive subjects. They suggest that hypertension is associated with a profound change in aortic wall mechanical properties possibly because of destruction of elastin leading to less strain-induced stiffening and predisposition to aortic dissection.

Identification of artery wall stiffness: in vitro validation and in vivo results of a data assimilation procedure applied to a 3D fluid-structure interaction model.

We consider the problem of estimating the stiffness of an artery wall using a data assimilation method applied to a 3D fluid-structure interaction (FSI) model. Recalling previous works, we briefly present the FSI model, the data assimilation procedure and the segmentation algorithm. We present then two examples of the procedure using real data. First, we estimate the stiffness distribution of a silicon rubber tube from image data. Second, we present the estimation of aortic wall stiffness from real clinical data.

Catheter-induced errors in pressure measurements in vessels: an in-vitro and numerical study.

Accurate measurement of blood pressure is important because it is a biomarker for cardiovascular disease. Diagnostic catheterization is routinely used for pressure acquisition in vessels despite being subject to significant measurement errors. To investigate these errors, this study compares pressure measurement using two different techniques in vitro and numerical simulations. Pressure was acquired in a pulsatile flow phantom using a 6F fluid-filled catheter and a 0.014'' pressure wire, which is considered the current gold standard. Numerical simulations of the experimental set-up with and without a catheter were also performed. Despite the low catheter-to-vessel radius ratio, the catheter traces showed a 24% peak systolic pressure overestimation compared to the wire. The numerical models replicated this difference and indicated the cause for overestimation was the increased flow resistance due to the presence of the catheter. Further, the higher frequency pressure oscillations observed in the wire and numerical data were absent in the catheter, resulting in an overestimation of the pulse wave velocity with the latter modality. These results show that catheter geometry produces significant measurement bias in both the peak pressure and the waveform shape even with radius ratios considered acceptable in clinical practice. The wire allows for more accurate pressure quantification, in agreement with the numerical model without a catheter.

Coronary vessel wall contrast enhancement imaging as a potential direct marker of coronary involvement: integration of findings from CAD and SLE patients.

OBJECTIVES: This study investigated the feasibility of visual and quantitative assessment of coronary vessel wall contrast enhancement (CE) for detection of symptomatic atherosclerotic coronary artery disease (CAD) and subclinical coronary vasculitis in autoimmune inflammatory disease (systemic lupus erythematosus [SLE]), as well as the association with aortic stiffness, an established marker of risk. BACKGROUND: Coronary CE by cardiac magnetic resonance (CMR) is a novel noninvasive approach to visualize gadolinium contrast uptake within the coronary artery vessel wall. METHODS: A total of 75 subjects (CAD: n = 25; SLE: n = 27; control: n = 23) underwent CMR imaging using a 3-T clinical scanner. Coronary arteries were visualized by a T2-prepared steady state free precession technique. Coronary wall CE was visualized using inversion-recovery T1 weighted gradient echo sequence 40 min after administration of 0.2 mmol/kg gadobutrol. Proximal coronary segments were visually examined for distribution of CE and quantified for contrast-to-noise ratio (CNR) and total CE area. RESULTS: Coronary CE was prevalent in patients (93%, n = 42) with a diffuse pattern for SLE and a patchy/regional distribution in CAD patients. Compared with control subjects, CNR values and total CE area in patients with CAD and SLE were significantly higher (mean CNR: 3.9 ± 2.5 vs. 6.9 ± 2.5 vs. 6.8 ± 2.0, respectively; p < 0.001; total CE area: median 0.8 [interquartile range (IQR): 0.6 to 1.2] vs. 3.2 [IQR: 2.6 to 4.0] vs. 3.3 [IQR: 1.9 to 4.5], respectively; p < 0.001). Both measures were positively associated with aortic stiffness (CNR: r = 0.61, p < 0.01; total CE area: 0.36, p = 0.03), hypercholesterolemia (r = 0.68, p < 0.001; r = 0.61, p < 0.001) and hypertension (r = 0.40, p < 0.01; r = 0.32, p < 0.05). CONCLUSIONS: We demonstrate that quantification of coronary CE by CNR and total CE area is feasible for detection of subclinical and clinical uptake of gadolinium within the coronary vessel wall. Coronary vessel wall CE may become an instrumental novel direct marker of vessel wall injury and remodeling in subpopulations at risk.

Aortic stiffness and interstitial myocardial fibrosis by native T1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy.

Increased aortic stiffness is related to increased ventricular stiffness and remodeling. Myocardial fibrosis is the pathophysiological hallmark of failing heart. We investigated the relationship between noninvasive imaging markers of myocardial fibrosis, native T1, and late gadolinium enhancement, respectively, and aortic stiffness in ventricular remodeling. Consecutive patients with known dilated cardiomyopathy (n=173) underwent assessment of cardiac volumes and function, T1 mapping, scar imaging, and pulse wave velocity, a measure of aortic stiffness. Asymptomatic healthy volunteers served as controls (n=47). Controls and patients showed an increase in pulse wave velocity with age, which was accelerated in the presence of cardiovascular disease. On the contrary, native T1 increased with age in patients, but not in controls. Pulse wave velocity was associated with native T1 in the presence of disease, but not in health. Native T1 showed a strong relationship with markers of structural and functional left ventricular remodeling and diastolic impairment. Ischemic and nonischemic pathophysiology of ventricular remodeling showed a similar slope of relationship between pulse wave velocity and native T1. However, in nonischemic patients, increase in pulse wave velocity was associated with greater increase in native T1. Aortic stiffness is related to age, and this process is accelerated in the presence of disease. On the contrary, increase in interstitial myocardial fibrosis is associated with age in the presence of disease. Patients with ischemic and nonischemic dilated cardiomyopathy have a similar relationship between native T1 and pulse wave velocity, which is stronger in the latter group.

Bisphosphonate-anchored PEGylation and radiolabeling of superparamagnetic iron oxide: long-circulating nanoparticles for in vivo multimodal (T1 MRI-SPECT) imaging.

The efficient delivery of nanomaterials to specific targets for in vivo biomedical imaging is hindered by rapid sequestration by the reticuloendothelial system (RES) and consequent short circulation times. To overcome these two problems, we have prepared a new stealth PEG polymer conjugate containing a terminal 1,1-bisphosphonate (BP) group for strong and stable binding to the surface of ultrasmall-superparamagnetic oxide nanomaterials (USPIOs). This polymer, PEG(5)-BP, can be used to exchange the hydrophobic surfactants commonly used in the synthesis of USPIOs very efficiently and at room temperature using a simple method in 1 h. The resulting nanoparticles, PEG(5)-BP-USPIOs are stable in water or saline for at least 7 months and display a near-zero ζ-potential at neutral pH. The longitudinal (r(1)) and transverse (r(2)) relaxivities were measured at a clinically relevant magnetic field (3 T), revealing a high r(1) of 9.5 mM(-1) s(-1) and low r(2)/r(1) ratio of 2.97, making these USPIOs attractive as T1-weighted MRI contrast agents at high magnetic fields. The strong T1-effect was demonstrated in vivo, revealing that PEG(5)-BP-USPIOs remain in the bloodstream and enhance its signal 6-fold, allowing the visualization of blood vessels and vascular organs with high spatial definition. Furthermore, the optimal relaxivity properties allow us to inject a dose 4 times lower than with other USPIOs. PEG(5)-BP-USPIOs can also be labeled using a radiolabeled-BP for visualization with single photon emission computed tomography (SPECT), and thus affording dual-modality contrast. The SPECT studies confirmed low RES uptake and long blood circulation times (t(1/2) = 2.97 h). These results demonstrate the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging agents for molecular imaging.

Gender-specific differences in myocardial deformation and aortic stiffness at rest and dobutamine stress.

Elderly women have increased aortic and ventricular stiffness but preserved global systolic function. Possible gender differences in ventricular deformation attributed to increased aortic stiffness at rest or with positive inotropic stress remain unknown. Eighty-four subjects (mean age: 63±8 years) were assessed for aortic stiffness by pulse wave velocity and ventricular deformation at rest and during dobutamine stress using magnetic resonance. At rest, women (n=40) had greater aortic stiffness and ventricular deformation than men (P<0.05). In men, dobutamine increased longitudinal (mean±SD: 3.3±4.1%; P<0.01) and circumferential deformation (2.9±5.1%; P=0.007), whereas women showed an increase in circumferential deformation only (4.8±6.3%; P<0.01). In men there was an inverse association between longitudinal deformation and pulse wave velocity at rest (r=-0.51; P=0.002) and linear at stress (r=0.52; P=0.001). In women there were no significant relations at rest, whereas at stress longitudinal deformation was inversely associated with pulse wave velocity (r=-0.43; P=0.02). We demonstrate gender-specific differences in the relationship between aortic stiffness and ventricular deformation at rest and during dobutamine stress. Although at rest longitudinal deformation is inversely related to aortic stiffness in men, there is no such relationship in women. At stress, men improve longitudinal function, whereas in women such response is limited.