Ralph Metcalfe’s research while affiliated with University of Houston and other places

Background Despite the fact that microvascular (endothelial) dysfunction is associated with various diseases from cardiovascular to kidney, lung, liver, and other medical conditions, it has not been extensively studied in various clinical and non-clinical settings as blood pressure has. Digital Thermal Flowmetry (DTF) of microvascular endothelial function is a new and automated technique based on monitoring fingertip temperature fall and rebound during reactive hyperemia. Here we report distributions of microvascular function across (1) CVD patients, (2) wellness and internal medicine clinics, (3) college students, and (4) community-based healthy volunteers in China. Methods A total of 7,907 endothelial function test results were collected from various settings. Blood pressure and heart rate were measured before the tests. The tests were conducted using FDA-approved automated VENDYS devices (Endothelix Inc., Palo Alto, CA). Adjusted maximum temperature rebound was reported as Vascular Reactivity Index (VRI) and compared across different settings. Results VRI in CVD patients, wellness and internal medicine clinics, college students, and Chinese volunteers were (1.25±0.34) (1.53±0.5) (1.86±0.5) (1.95±0.44.) respectively P<0.01. Age was weakly correlated with VRI with the equation age=-0.01 VRI+2.01 (r=0.17 p<0.001) Conclusions To our knowledge, this is the largest database of finger-based endothelial function testing. VRI showed distinct distributions across various clinical and non-clinical settings with CVD patients exhibiting the lowest and Chinese healthy volunteers the highest values. The VRI trend mimics the statistically expected risk trend with CVD patients having the highest and Chinese healthy volunteers having the lowest CVD events risk.Figure 1.

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean±SD of 1.58±0.53 in Registry-I and 1.52±0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men (1.62±0.56 vs. 1.54±0.47, p<0.001). VRI was inversely but mildly correlated with age (r=−0.19, p<0.001). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

Left ventricular assist devices (LVADs) are increasingly used to treat heart failure patients. These devices’ impeller blades and diffuser vanes must be designed for hydraulic performance and hemocompatibility. The traditional design method, applying mean-line theory, is not applicable to the design of small-scale pumps such as miniature LVADs. Furthermore, iterative experimental testing to determine how each geometric variable affects hydraulic performance is time and labor intensive. In this study, we tested a design method wherein empirical hydraulic results are used to establish a statistical model to predict pump hydraulic performance. This method was used to design an intra-atrial blood pump. Five geometric variables were chosen, and each was assigned two values to define the variable space. The experimental results were then analyzed with both correlation analysis and linear regression modeling. To validate the linear regression models, 2 test pumps were designed: mean value of each geometric variable within the boundaries, and random value of each geometric variable within the boundaries. The statistical model accurately predicted the hydraulic performance of both pump designs within the boundary space. This method could be expanded to include more geometric variables and broader boundary conditions, thus accelerating the design process for miniature LVADs.

An intra-atrial pump (IAP) was proposed that would be affixed to the atrial septum to support the compromised left ventricle (LV) without harming the ventricular tissue in patients with early-stage heart failure. The IAP is designed to operate in parallel with the LV, drawing blood from the left atrium and unloading the LV. In previous hydraulic studies, different blade geometries were tested for the IAP; however, it is important to know how the blade geometry affects the IAP's hemodynamic performance in the human cardiovascular system. In this study, a mock circulatory loop (MCL) with physiological response was used to evaluate the hemodynamic effects of IAP blade geometry and connection configuration in the human cardiovascular system. In a $2 \times 2$ study, two different blade geometries (with steep vs flat pressure/flow curves) were tested in two different connection configurations: the proposed configuration (left atrium to aorta) and the conventional configuration for LVADs (LV to aorta). We found that atrial cannulation is feasible and creates a beneficial hemodynamic environment, although it is inferior to the one created by ventricular cannulation. The steepgradient pump performed better than the flat-gradient pump in atrial insertion.

Purpose: A minimally invasive, partial-assist, intra-atrial blood pump has been proposed, which would unload the left ventricle with a flow path from the left atrium to the arterial system. Flow modulation is a common strategy for ensuring washout in the pump, but it can increase power consumption because it is typically achieved through motor-speed variation. However, if a pump's performance curve had the proper gradient, flow modulation could be realized passively. To achieve this goal, we propose a pump performance operating curve as an alternative to the more standard operating point. Methods and results: Mean-line theory was employed to generate an initial set of geometries that were then tested on a hydraulic test rig at ~20,000 r/min. Experimental results show that the intra-atrial blood pump performed below the operating region; however, it was determined that smaller hub diameter and longer chord length bring the performance of the intra-atrial blood pump device closer to the operating curve. Conclusion: We found that it is possible to shape the pump performance curve for specifically targeted gradients over the operating region through geometric variations inside the pump.

Restenosis rates caused by neointimal hyperplasia are relatively high (˜30%) after stent implantation in stenosed arteries. The flow around stent struts under steady and unsteady conditions using computational hemodynamics (CHD) was studied to identify contributing factors to the formation of low and oscillating wall shear stress regions that have been shown to promote endothelial dysfunction and atherosclerotic plaque formation in arteries. Datasets of the Neuroform, BxVelocity, and Taxus stents deployed in straight polymer tubes were obtained from high resolution micro computed tomography. Finite volume CHD simulations of steady and unsteady flow with and without flow reversal were performed. Stagnation zones were noticed adjacent to the strut junctions as the flow enters and exits the stent cells. The stagnation zones were larger in the case of the stents with larger strut diameter (BxVelocity, Taxus), wider strut junctions and larger angles between the struts. Unsteady flow simulations showed enhanced flow reversal with thicker struts and large regions of recirculation flow developing inside the stent at Reynolds numbers higher than 200. It was shown that alterations in blood flow due to real stent deployment (strut prolapse, junction misalignment) cannot be captured with computer generated stent models, that stent specific geometry, and time dependent flow effects can locally alter the wall shear stress and stagnation zones.

Small metallic stents are increasingly used in the treatment of cerebral aneurysms and for revascularization in ischemic strokes. Realistic three-dimensional datasets of a stent were obtained by using three x-ray-based imaging methods in current clinical use. Multislice-CT (MS-CT), C-arm flat detector-CT (C-arm CT, ACT), and flat panel-CT (FP-CT) were compared with high-resolution laboratory MicroCT scans that served as a reference standard. The purpose was to assess and compare the quality and accuracy of current clinical three-dimensional reconstructions of a vascular stents. A 3 × 20 mm Cypher stent was deployed in a straight polytetrafluoroethylene tube and filled with nondiluted iodine contrast and BaSO(4). MS-CT images of the static tube phantom and stent were acquired using GE LightSpeed VCT Series, C-arm CT images were obtained using Artis (DynaCT, Siemens), FP-CT were obtained using a preclinical research CT (GE), and MicroCT images were obtained using eXplore Locus SP (GE). DICOM datasets were analyzed using Amira and Matlab. Because of blooming effects, the maximum intensity projections (MIPs) and volume renderings generated from MS-CT showed significantly increased strut dimensions with no distinction between the regular struts and connector struts while the lumen diameter is artificially reduced. The shape of the reconstructed stent surface differed remarkably from the real stent. C-arm CT and FP-CT volume renderings more accurately represented the struts. Consistently capturing the structure of the connectors and the strut shape definition was highly threshold dependent. The stent lumen was about 30% underestimated by MS-CT when compared to MicroCT. The spatial resolution of current clinical CT for imaging of small metallic stents is insufficient to visualize fine geometrical details. Further improvement in the spatial resolution of clinical imaging technologies combined with better software and hardware for image postprocessing will be necessary for detailed structural analysis, evaluation of the stent lumen in vivo, and to permit accurate assessment of stent patency and early detection potential in-stent stenosis.

Both structural and functional evaluations of the endothelium exist in order to diagnose cardiovascular disease (CVD) in its asymptomatic stages. Vascular reactivity, a functional evaluation of the endothelium in response to factors such as occlusion, cold, and stress, in addition to plasma markers, is the most widely accepted test and has been found to be a better predictor of the health of the endothelium than structural assessment tools such as coronary calcium scores or carotid intima-media thickness. Among the vascular reactivity assessment techniques available, digital thermal monitoring (DTM) is a noninvasive technique that measures the recovery of fingertip temperature after 2-5 min of brachial occlusion. On release of occlusion, the finger temperature responds to the amount of blood flow rate overshoot referred to as reactive hyperemia (RH), which has been shown to correlate with vascular health. Recent clinical trials have confirmed the potential importance of DTM as an early stage predictor of CVD. Numerical simulations of a finger were carried out to establish the relationship between DTM and RH. The model finger consisted of essential components including bone, tissue, major blood vessels (macrovasculature), skin, and microvasculature. The macrovasculature was represented by a pair of arteries and veins, while the microvasculature was represented by a porous medium. The time-dependent Navier-Stokes and energy equations were numerically solved to describe the temperature distribution in and around the finger. The blood flow waveform postocclusion, an input to the numerical model, was modeled as an instantaneous overshoot in flow rate (RH) followed by an exponential decay back to baseline flow rate. Simulation results were similar to clinically measured fingertip temperature profiles in terms of basic shape, temperature variations, and time delays at time scales associated with both heat conduction and blood perfusion. The DTM parameters currently in clinical use were evaluated and their sensitivity to RH was established. Among the parameters presented, temperature rebound (TR) was shown to have the best correlation with the level of RH with good sensitivity for the range of flow rates studied. It was shown that both TR and the equilibrium start temperature (representing the baseline flow rate) are necessary to identify the amount of RH and, thus, to establish criteria for predicting the state of specific patient's cardiovascular health.

Digital thermal monitoring (DTM) is a noninvasive, inexpensive, easily performed, operator-independent vascular function test designed to complement the existing, risk-factor based assessment of vascular health and to monitor the vascular response to therapies. It is similar to a blood pressure device, with the addition of adhesive temperature probes on the right and left index fingertips that measure fingertip temperature fall and rebound during a brief (2–5 min), arm-cuff occlusion, and release procedure (reactive hyperemia). The higher the temperature rebound, the better the vascular reactivity. In our studies, we have found that DTM indices of vascular reactivity correlate strongly with the number of cardiovascular risk factors, measured by the Framingham Risk Score (FRS), and with the burden of asymptomatic (subclinical) coronary atherosclerosis, measured by coronary calcium score and CT angiography, as well as with myocardial perfusion defects on nuclear stress testing in symptomatic subjects. Moreover, our studies have shown that DTM provides incremental predictive value over risk factor assessment for the identification of high-risk patients with both subclinical atherosclerosis (Coronary Artery Calcium Score ≥100) and coronary artery stenosis (CT angiography showing ≥ 50% stenosis). Finally, DTM indices of vascular function have shown reproducibility comparable to blood pressure measurements. These very promising findings will require corroboration, particularly in long-term, prospective studies and clinical trials. It is important to emphasize that DTM is not intended to replace measurement of risk factors or advanced imaging tests. Rather, its purpose is to complement them by providing a powerful, noninvasive vascular function assessment of coronary health. Key wordsDigital (fingertip) thermal monitoring (DTM)-Framingham risk score-Coronary calcium score-Vascular function-Endothelial dysfunction-Reactive hyperemia-Vascular reactivity

The majority of acute coronary syndromes are the result of coronary plaque rupture. Recent studies have revealed the presence of neovascularization in and around the plaque to be a common feature of presumed rupture-prone (vulnerable) plaques. Intravascular ultrasound combined with contrast enhancement agents has been shown to be useful for the detection and quantification of vasa vasorum (VV) and angiogenesis within the vessel wall. In this chapter, the two state-of-the-art techniques for VV imaging are reviewed. Key wordsACES-Cardiovascular disease-Contrast-enhanced intravascular ultrasound-Image analysis-IVUS-Microbubbles-Neoangiogenesis-Neovascularization-Plaque rupture-Vasa vasorum-Vulnerable plaque-VV