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Labarrere C.A.,California Medical Innovations Institute | Jaeger B.R.,Medical Care Center | Kassab G.S.,California Medical Innovations Institute
Frontiers in Bioscience - Elite | Year: 2017

Cardiac allograft vasculopathy (CAV) is a serious complication of heart transplantation in adults and children. Risk factors include human leukocyte antigen mismatches, number and duration of rejection episodes, type of immunosuppression, antibodymediated rejection, hypertension, hyperlipidemia, obesity, smoking, diabetes, cytomegalovirus infection, mode of donor brain death, donor age and ischemia/reperfusion injury. Endothelial injury and dysfunction in CAV are characterized by changes in adhesion molecules and up-regulation of major histocompatibility class II antigens followed by endothelial activation of complement C4d. Subsequently, activation of the coagulation cascade leads to deposition of fibrin on endothelium followed by proliferation and migration of vascular smooth muscle cells. The development of a special type of microvessels with phenotypic characteristics of arterial capillaries ("capioles") seems to provide a survival advantage for patients with CAV. Novel therapies of CAV include statins, and heparin-induced extracorporeal low-density lipoprotein apheresis. Bbeta15-42 which is a fibrin peptide has been shown to improve the graft microvasculature and to reduce ischemia/reperfusion-induced damage. Despite these advances, there is a need to identify and stratify individual CAV risk factors, to develop early biomarkers of CAV, and to better decipher the events that lead to antibody-mediated rejection.

Patel B.,California Medical Innovations Institute | Ahuja A.,California Medical Innovations Institute | Kassab G.S.,California Medical Innovations Institute | Labarrere C.A.,California Medical Innovations Institute
Frontiers in Bioscience - Elite | Year: 2017

Cardiac allograft vasculopathy (CAV) is one of the most common long-term complications in patients following heart transplantation. Because of its irreversible nature, early detection is essential to impact progression. Thus, imaging techniques play a crucial role in the diagnosis and subsequent treatment. Major advancements in imaging and analysis are required to overcome the limitations of current techniques. Coronary angiography which is the standard method, presents low sensitivity in detection, especially at an early stage. Intravascular ultrasonography is a more reliable alternative but is limited to the epicardial vessels. Novel non-invasive techniques, such as stress echocardiography and nuclear imaging, have been introduced but not without limitations. Here, we review various imaging methods and associated analyses to improve diagnostic predictions. We discuss recent advances in the diagnosis of coronary artery disease and their potential translation in the diagnosis of CAV. Additionally, we present potential biomarkers that have been identified for CAV. Finally, we provide a discussion on microvessels with novel anticoagulant properties that are mostly identified in patients with severe CAV.

Huo Y.,Peking University | Huo Y.,Hebei University | Kassab G.S.,California Medical Innovations Institute
Journal of Applied Physiology | Year: 2015

Congestive heart failure (CHF) is a very serious heart disease that manifests an imbalance between left ventricle supply and demand. Although the mechanical demand of the failing heart has been well characterized, the systematic remodeling of the entire coronary arterial tree that constitutes the supply of the myocardium is lacking. We hypothesize that the well-known increase in ventricle wall stress during CHF causes coronary vascular rarefaction to increase the vascular flow resistance, which in turn compromises the perfusion of the heart. Morphometric (diameters, length, and numbers) data of the swine left circumflex (LCx) arterial tree were measured in both CHF (n = 6) and control (n = 6) groups, from which a computer reconstruction of the entire LCx tree was implemented down to the capillary level to enable a hemodynamic analysis of coronary circulation. The vascular flow resistance was increased by ∼75% due to a significant decrease of vessel numbers (∼45%) and diameters in the first capillary segments (∼10%) of the LCx arterial tree after 3-4 wk of pacing. The structural remodeling significantly changed the wall shear stress in vessel segments of the entire LCx arterial tree of CHF animals. This study enhances our knowledge of coronary arterial tree remodeling in heart failure, which provides a deeper understanding of the deterioration of supply-demand relation in left ventricle. Copyright © 2015 the American Physiological Society.

Huo Y.,Peking University | Huo Y.,Hebei University | Kassab G.S.,California Medical Innovations Institute
Journal of Biomechanics | Year: 2016

The heterogeneity and complexity of coronary vasculature (structure) and myocardial flow (function) have fractal-like characteristics and can be described by scaling laws with remarkable simplicity. In contrast with allometric (interspecific) scaling law, intraspecific scaling laws describe the design rules of vascular trees within a species. This paper provides an overview of intraspecific scaling laws of vascular trees and the physiological and clinical implications thereof. The significance and shortcomings of these scaling laws are discussed in relation to diffuse coronary artery disease, Glagov's positive remodeling in early stages of coronary atherosclerosis, treatment guidelines of complex bifurcation lesions, and for estimation of outlet resistance values for computation of blood flow in epicardial coronary arteries. Finally, we summarize the highlights of scaling relations and suggest some future directions. © 2016 Elsevier Ltd.

PubMed | University of Minnesota, California Medical Innovations Institute, University of Pennsylvania, Boston University and 6 more.
Type: Journal Article | Journal: Annals of biomedical engineering | Year: 2016

Cardiovascular diseases (CVDs) are the leading cause of death in the western world. With the current development of clinical diagnostics to more accurately measure the extent and specifics of CVDs, a laudable goal is a better understanding of the structure-function relation in the cardiovascular system. Much of this fundamental understanding comes from the development and study of models that integrate biology, medicine, imaging, and biomechanics. Information from these models provides guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting, in turn, provides data for refining the models. In this review, we introduce multi-scale and multi-physical models for understanding disease development, progression, and designing clinical interventions. We begin with multi-scale models of cardiac electrophysiology and mechanics for diagnosis, clinical decision support, personalized and precision medicine in cardiology with examples in arrhythmia and heart failure. We then introduce computational models of vasculature mechanics and associated mechanical forces for understanding vascular disease progression, designing clinical interventions, and elucidating mechanisms that underlie diverse vascular conditions. We conclude with a discussion of barriers that must be overcome to provide enhanced insights, predictions, and decisions in pre-clinical and clinical applications.

Kassab G.S.,Indiana University – Purdue University Indianapolis | Kassab G.S.,California Medical Innovations Institute
Drug Discovery Today: Disease Models | Year: 2014

Ischemic heart disease (IHD) is a major cause of morbidity and mortality in the world. The use of mathematical models allows the integration of the structural/mechanical/biochemical determinants of coronary flow for understanding coronary physiology/pathophysiology as well as to provide avenues for diagnosis and therapy of IHD. This review provides an overview of coronary flow models in the deep layers of the heart that are vulnerable to ischemia and models for non-invasive determination of ischemic severity. © 2014 Elsevier Ltd.

Kassab G.S.,California Medical Innovations Institute | Finet G.,Cardiovascular Hospital
EuroIntervention | Year: 2015

The study of the structure-function relation of coronary bifurcations is necessary not only to understand the design of the vasculature but also to use this understanding to restore structure and hence function. The objective of this review is to provide quantitative relations between bifurcation anatomy or geometry, flow distribution in the bifurcation and degree of perfused myocardial mass in order to establish practical rules to guide optimal treatment of bifurcations including side branches (SB). We use the scaling law between flow and diameter, conservation of mass and the scaling law between myocardial mass and diameter to provide geometric relations between the segment diameters of a bifurcation, flow fraction distribution in the SB, and the percentage of myocardial mass perfused by the SB. We demonstrate that the assessment of the functional significance of an SB for intervention should not only be based on the diameter of the SB but also on the diameter of the mother vessel as well as the diameter of the proximal main artery, as these dictate the flow fraction distribution and perfused myocardial mass, respectively. The geometric and flow rules for a bifurcation are extended to a trifurcation to ensure optimal therapy scaling rules for any branching pattern. © 2015 Europa Digital & Publishing. All rights reserved.

Chen H.,California Medical Innovations Institute | Guo X.,California Medical Innovations Institute | Luo T.,California Medical Innovations Institute | Kassab G.S.,California Medical Innovations Institute
Journal of Applied Physiology | Year: 2016

A structure-based model that accurately predicts micro-or macromechanical behavior of blood vessels is necessary to understand vascular physiology. Based on recently measured microstructural data, we propose a three-dimensional microstructural model of coronary adventitia that incorporates the elastin and collagen distributions throughout the wall. The role of ground substance was found to be negligible under physiological axial stretch z 1.3, based on enzyme degradation of glycosaminoglycans in swine coronary adventitia (n=5). The thick collagen bundles of outer adventitia (n=4) were found to be undulated and unengaged at physiological loads, whereas the inner adventitia consisted of multiple sublayers of entangled fibers that bear the majority of load at higher pressures. The microstructural model was validated against biaxial (inflation and extension) experiments of coronary adventitia (n=5). The model accurately predicted the nonlinear responses of the adventitia, even at high axial force (axial stretch ratio z 1.5). The model also enabled a reliable estimation of material parameters of individual fibers that were physically reasonable. A sensitivity analysis was performed to assess the effect of using mean values of the distributions for fiber orientation and waviness as opposed to the full distributions. The simplified mean analysis affects the fiber stress-strain relation, resulting in incorrect estimation of mechanical parameters, which underscores the need for measurements of fiber distribution for a rigorous analysis of fiber mechanics. The validated structure-based model of coronary adventitia provides a deeper understanding of vascular mechanics in health and can be extended to disease conditions. Copyright © 2016 the American Physiological Society.

PubMed | California Medical Innovations Institute, A-Life Medical, Indiana University, Wayne State University and 3 more.
Type: | Journal: American journal of obstetrics and gynecology | Year: 2016

Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 (ICAM-1) expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. ICAM-1-overexpressing activated endothelial cells are more resistant to trophoblast displacement than non-activated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation.To determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate.A cross-sectional study of 123 placentas (19 to 42 weeks gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15) and small for gestational age (n = 10), was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of ICAM-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fishers exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (0.025).We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the ICAM-1 activation marker (P < 0.001). A significant correlation (RFailure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic and other abnormal pregnancies.

PubMed | Indiana University, California Medical Innovations Institute and West Virginia University
Type: Journal Article | Journal: Basic research in cardiology | Year: 2016

Ion channels in smooth muscle control coronary vascular tone, but the identity of the potassium channels involved requires further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P<0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels. Whole-cell patch-clamp experiments demonstrated significant correolide-sensitive (1-10M) current in coronary smooth muscle. In vivo studies included direct intracoronary infusion of vehicle or correolide into a pressure-clamped left anterior descending artery of healthy swine (n=5 in each group) with simultaneous measurement of coronary blood flow. Intracoronary correolide (~0.3-3M targeted plasma concentration) had no effect on heart rate or systemic pressure, but reduced coronary blood flow in a dose-dependent manner (P<0.05). Dobutamine (0.3-10g/kg/min) elicited coronary metabolic vasodilation and intracoronary correolide (3M) significantly reduced coronary blood flow at any given level of myocardial oxygen consumption (P<0.001). Coronary artery occlusions (15s) elicited reactive hyperemia and correolide (3M) reduced the flow volume repayment by approximately 30% (P<0.05). Taken together, these data support a major role for KV1 channels in modulating baseline coronary vascular tone and, perhaps, vasodilation in response to increased metabolism and transient ischemia.

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