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Background: As of 2016, ≈1.4 million people in the United States identify as transgender. Despite their growing number and increasing specific medical needs, there has been a lack of research on cardiovascular disease (CVD) and CVD risk factors in this population. Recent studies have reported that the transgender population had a significantly higher rate of CVD risk factors without a significant increase in overall CVD morbidity and mortality. These studies are limited by their small sample sizes and their predominant focus on younger transgender populations. With a larger sample size and inclusion of broader age range, our study aims to provide insight into the association between being transgender and cardiovascular risk factors, as well as myocardial infarction., Methods and Results: The Behavioral Risk Factor Surveillance System data from 2014 to 2017 were used to evaluate the cross-sectional association between being transgender and the reported history of myocardial infarction and CVD risk factors. A logistic regression model was constructed to study the association between being transgender and myocardial infarction after adjusting for CVD risk factors including age, diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease, smoking, and exercise. Multivariable analysis revealed that transgender men had a >2-fold and 4-fold increase in the rate of myocardial infarction compared with cisgender men (odds ratio, 2.53; 95% CI, 1.14-5.63; P=0.02) and cisgender women (odds ratio, 4.90; 95% CI, 2.21-10.90; P<0.01), respectively. Conversely, transgender women had >2-fold increase in the rate of myocardial infarction compared with cisgender women (odds ratio, 2.56; 95% CI, 1.78-3.68; P<0.01) but did not have a significant increase in the rate of myocardial infarction compared with cisgender men., Conclusions: The transgender population had a higher reported history of myocardial infarction in comparison to the cisgender population, except for transgender women compared with cisgender men, even after adjusting for cardiovascular risk factors.

The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies. In vivo left-ventricular hemodynamics/pressure-volume relationships assessed before/during a 30 min IV infusion of CXL-1020 demonstrated acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats. In rats with only diastolic dysfunction due to bilateral renal wrapping (RW) or pronounced diastolic and mild systolic dysfunction due to 4 weeks of chronic isoproterenol exposure (ISO), CXL-1020 attenuated the elevated LV filling pressures, improved the end diastolic pressure volume relationship, and accelerated relaxation. CXL-1020 facilitated Ca 2+ re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca 2+ reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca 2+ entry via L-type Ca 2+ channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca 2+ cycling, in the setting of chronic induced diastolic dysfunction. CXL-1020's lusitropic effects were greater than those seen with the cAMP-dependent agent milrinone, and unlike milrinone it did not produce chronotropy or increased ectopy. HNO is a promising new potential therapy for both systolic and diastolic heart failure.

Background: Currently, there are limited means for high-resolution monitoring of tissue injury during radiofrequency ablation procedures., Objective: To develop the next generation of visualization catheters that can reveal irreversible atrial muscle damage caused by ablation and identify viability gaps between the lesions., Methods: Radiofrequency lesions were placed on the endocardial surfaces of excised human and bovine atria and left ventricles of blood perfused rat hearts. Tissue was illuminated with 365nm light and a series of images were acquired from individual spectral bands within 420-720nm range. By extracting spectral profiles of individual pixels and spectral unmixing, the relative contribution of ablated and unablated spectra to each pixel was then displayed. Results of spectral unmixing were compared to lesion pathology., Results: RF ablation caused significant changes in the tissue autofluorescence profile. The magnitude of these spectral changes in human left atrium was relatively small (< 10% of peak fluorescence value), yet highly significant. Spectral unmixing of hyperspectral datasets enabled high spatial resolution, in-situ delineation of radiofrequency lesion boundaries without the need for exogenous markers. Lesion dimensions derived from hyperspectral imaging approach strongly correlated with histological outcomes. Presence of blood within the myocardium decreased the amplitude of the autofluorescence spectra while having minimal effect on their overall shapes. As a result, the ability of hyperspectral imaging to delineate ablation lesions in vivo was not affected., Conclusions: Hyperspectral imaging greatly increases the contrast between ablated and unablated tissue enabling visualization of viability gaps at clinically relevant locations. Data supports the possibility for developing percutaneous hyperspectral catheters for high-resolution ablation guidance., Competing Interests: I have read the journal's policy. The authors of this manuscript do not have any competing interests. Mercader & Sarvazyan have ownership of LuxCath LLC stock options which does not alter authors' adherence to PLOS ONE policies on sharing data and materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.

Background: Studies with other imaging modalities have demonstrated a relationship between contrast transit and cardiac output (CO) and pulmonary vascular resistance (PVR). We tested the hypothesis that the transit time during contrast echocardiography could accurately estimate both CO and PVR compared to right heart catheterization (RHC)., Methods: 27 patients scheduled for RHC had 2D-echocardiogram immediately prior to RHC. 3 ml of DEFINITY contrast followed by a 10 ml saline flush was injected, and a multi-cycle echo clip was acquired from the beginning of injection to opacification of the left ventricle. 2D-echo based calculations of CO and PVR along with the DEFINITY-based transit time calculations were subsequently correlated with the RHC-determined CO and PVR., Results: The transit time from full opacification of the right ventricle to full opacification of the left ventricle inversely correlated with CO (r=-0.61, p<0.001). The transit time from peak opacification of the right ventricle to first appearance in the left ventricle moderately correlated with PVR (r=0.46, p<0.01). Previously described echocardiographic methods for the determination of CO (Huntsman method) and PVR (Abbas and Haddad methods) did not correlate with RHC-determined values (p = 0.20 for CO, p = 0.18 and p = 0.22 for PVR, respectively). The contrast transit time method demonstrated reliable intra- (p<0.0001) and inter-observer correlation (p<0.001)., Conclusions: We describe a novel method for the quantification of CO and estimation of PVR using contrast echocardiography transit time. This technique adds to the methodologies used for noninvasive hemodynamic assessment, but requires further validation to determine overall applicability.

Background: The nitroxyl (HNO) donor, Angeli's salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF)., Methods and Results: CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50-500 μmol/L), with a ≈30% rise in the peak Ca(2+) transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular end-diastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance and provided venoarterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly., Conclusions: These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function and present first-in-man evidence for its potential usefulness in HF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.

The possibility of using stem cells to regenerate damaged myocardium has been actively investigated since the late 1990s. Consistent with the traditional view that the heart is a "postmitotic" organ that possesses minimal capacity for self-repair, much of the preclinical and clinical work has focused exclusively on introducing stem cells into the heart, with the hope of differentiation of these cells into functioning cardiomyocytes. This approach is ongoing and retains promise but to date has yielded inconsistent successes. More recently, it has become widely appreciated that the heart possesses endogenous repair mechanisms that, if adequately stimulated, might regenerate damaged cardiac tissue from in situ cardiac stem cells. Accordingly, much recent work has focused on engaging and enhancing endogenous cardiac repair mechanisms. This article reviews the literature on stem cell-based myocardial regeneration, placing emphasis on the mutually enriching interaction between basic and clinical research., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is increasing in prevalence. Although experienced centers performing radiofrequency pulmonary vein isolation procedures have reported success rates approaching 72%, in rare instances it is complicated by stenosis of one or more pulmonary veins. In this report we present a case of recurrent pulmonary vein stenosis (PVS) following radiofrequency ablation for AF.

Congestive heart failure accounts for tremendous morbidity and mortality worldwide. There are numerous causes of cardiomyopathy, the most common of which is coronary artery disease. Positron emission tomography (PET) has an established and expanding role in the evaluation of patients with cardiomyopathy. The specific application of PET to hypertrophic cardiomyopathy, cardiac sarcoidosis, and diabetic cardiomyopathy has been studied extensively and promises to be a useful tool for managing these patients. Furthermore, evaluating the efficacy of standard treatments for congestive heart failure is important as health care costs continue to rise. Recently, there have been significant developments in the field of cardiovascular stem cell research. Familiarity with the mechanisms by which stem cells benefit patients with cardiovascular disease is the key to understanding these advances. Molecular imaging techniques including PET/CT imaging play an important role in monitoring stem cell therapy in both animals and humans. These noninvasive imaging techniques will be highlighted in this paper., (© 2011 New York Academy of Sciences.)

Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes., Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire., Methods and Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit(+) CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4(+) CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit(+) CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I., Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

Congestive heart failure and coronary artery disease are the leading causes of morbidity and mortality in the United States despite substantial therapeutic advances in the last half century. Only very recently have studies arisen that support possibility of regenerating tissue of damaged human organs including the heart. In this regard, there is growing pre-clinical and clinical evidence demonstrating the safety and efficacy of cell-based myocardial regeneration using a variety of cell lines. Although the data on the exact mechanism of action and the fate of the administered cells is controversial, there is consistent evidence for improved cardiac function and myocardial regeneration using different cell types. This extraordinarily exciting scientific advance has forced cardiovascular scientists to re-evaluate the long-held paradigm of cardiac myocyte terminal differentiation and life-long longevity of the cardiac myocytes that comprise the heart. Whereas, these new ideas originated with attempts to perform cellular transplantation using exogenous stem or precursor cells, mechanistic insights have rapidly evolved to the realization that adult organs harbor stem cells with significant plasticity, capable of repopulating their respective organ. Indeed these cells may be harnessed as a therapeutic agent or may represent the target of regenerative therapeutic strategies.

Clinical and basic studies of cell-based myocardial therapy have proceeded at a rapid pace. Cell therapy could lead to successful cardiac regeneration or repair by any of three general mechanisms: differentiation of the administered cells into all of the cellular constituents of the heart; release of factors capable of paracrine signaling from the administered cells; and fusion of the administered cells with the existing constituents of the heart. Here, we argue that a fourth general mechanism could be operative: stimulation of endogenous repair by injected cells, which and might cause the regeneration of stem cell niches. In a porcine model of myocardial infarction, allogeneic mesenchymal stem cells stimulated substantial improvement in the ejection fraction, reduction of infarct size, and the growth of a rim of new cardiac tissue in the region in which the mesenchymal stem cells were injected. These effects occurred in the absence of definitive cardiac myocyte differentiation. After myocardial infarction, porcine hearts exhibit evidence of cardiac myocytes that have entered the cell cycle, neovascularization, and reduced levels of apoptosis. These data, in addition to new insights regarding the presence of endogenous cardiac stem cells, strongly support the concept that the heart could contain stem cell niches. Effective cell therapy could lead to restoration of these niches through multifaceted cell-cell interactions.

Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6- and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit(+) cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.

Background: Acute renal failure (ARF) occurs commonly in the intensive care unit (ICU), but predicting which patients will develop ARF is difficult. We set out to determine which risk factors would predict the development of ARF in critically ill patients who are admitted to the ICU without ARF., Methods: From August 2002 to April 2003, we enrolled medical-surgical ICU admissions into a cohort using a sampling tool based on their risk factor (RF) profile. The risk factors we identified were separated into 3 categories: chronic major, chronic minor, and acute RFs. Combinations of these RFs were used to create a sampling tool and identify patients to enroll into our cohort. Patients with end-stage renal disease and ARF upon admission to the ICU were excluded., Results: We enrolled 194 patients over a 14-month period. The mean age of the cohort was 64.6 +/- 14.7 years. The percentage of Caucasians, African Americans, and Hispanics was 40.7%, 50.5%, and 3.6%, respectively. In a univariate analysis of the entire cohort, increasing APACHE II quartile, increased A-a gradient, presence of systemic inflammatory response syndrome (SIRS), decreased levels of serum albumin, and presence of active cancer predicted ARF. In a multiple logistic regression analysis, decreased serum albumin (high levels of serum albumin were protective), increased A-a gradient, and cancer were associated with development of ARF (OR 2.17, 1.04, and 2.86, respectively)., Conclusion: Decreased levels of serum albumin concentration, increased A-a gradient, and presence of active cancer predict which patients who are admitted to the ICU will develop ARF.

Peripheral arterial disease (PAD), like coronary heart disease, is a clinical manifestation of atherosclerosis and is associated with increased mortality. Although atherosclerotic cardiovascular disease is the leading cause of death for women as well as for men, PAD in women has received less attention than coronary heart disease or stroke. This paper reviews the prevalence of PAD, its risk factors, clinical significance, and management in women. One gender-specific therapeutic issue of particular interest to practitioners and the lay public is the role of postmenopausal hormone therapy. Prior to completion of the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Hormone Trials, postmenopausal hormone therapy was believed to exert antiatherosclerotic effects and to thereby reduce coronary heart disease risk in women on the basis of case-control and cohort studies. This review particularly focuses on the role, if any, of postmenopausal hormone therapy for prevention or treatment of PAD, which was a pre-specified secondary outcome for these three randomized trials.

A computational model of the human left-ventricular epicardial myocyte is presented. Models of each of the major ionic currents present in these cells are formulated and validated using experimental data obtained from studies of recombinant human ion channels and/or whole-cell recording from single myocytes isolated from human left-ventricular subepicardium. Continuous-time Markov chain models for the gating of the fast Na(+) current, transient outward current, rapid component of the delayed rectifier current, and the L-type calcium current are modified to represent human data at physiological temperature. A new model for the gating of the slow component of the delayed rectifier current is formulated and validated against experimental data. Properties of calcium handling and exchanger currents are altered to appropriately represent the dynamics of intracellular ion concentrations. The model is able to both reproduce and predict a wide range of behaviors observed experimentally including action potential morphology, ionic currents, intracellular calcium transients, frequency dependence of action-potential duration, Ca(2+)-frequency relations, and extrasystolic restitution/post-extrasystolic potentiation. The model therefore serves as a useful tool for investigating mechanisms of arrhythmia and consequences of drug-channel interactions in the human left-ventricular myocyte.

Regulatory subunit KCNE3 (E3) interacts with KCNQ1 (Q1) in epithelia, regulating its activation kinetics and augmenting current density. Since E3 is expressed weakly in the heart, we hypothesized that ectopic expression of E3 in cardiac myocytes might abbreviate action potential duration (APD) by interacting with Q1 and augmenting the delayed rectifier current (I(K)). Thus, we transiently coexpressed E3 with Q1 and KCNE1 (E1) in Chinese hamster ovary cells and found that E3 coexpression increased outward current at potentials by > or = -80 mV and accelerated activation. We then examined the changes in cardiac electrophysiology following injection of adenovirus-expressed E3 into the left ventricular cavity of guinea pigs. After 72 hours, the corrected QT interval of the electrocardiogram was reduced by approximately 10%. APD was reduced by >3-fold in E3-transduced cells relative to controls, while E-4031-insensitive I(K) and activation kinetics were significantly augmented. Based on quantitative modeling of a transmural cardiac segment, we demonstrate that the degree of QT interval abbreviation observed results from electrotonic interactions in the face of limited transduction efficiency and that heterogeneous transduction of E3 may actually potentiate arrhythmias. Provided that fairly homogeneous ectopic ventricular expression of regulatory subunits can be achieved, this approach may be useful in enhancing repolarization and in treating long QT syndrome.

Background: Regional function in stunned myocardium is usually thought to be more depressed in the endocardium than the epicardium. This has been attributed to the greater loss of blood flow at the endocardium during ischemia., Methods and Results: We measured transmural distributions of 3D systolic strains relative to local myofiber axes in open-chest anesthetized dogs before 15 minutes of left anterior descending coronary artery occlusion and during 2 hours of reperfusion. During ischemia, regional myocardial blood flow was reduced 84% at the endocardium and 32% at the epicardium (P<0.005, n=7), but changes in end-systolic fiber length from baseline were transmurally uniform. Relative to baseline, radial segments in stunned tissue were significantly thinner at the endocardium than the epicardium at end systole (24+/-5% versus 16+/-3%; P<0.05, n=8), consistent with previous reports. Unlike radial and cross-fiber segments, however, the increase of end-systolic fiber lengths in stunned myocardium had no significant transmural gradient (23+/-8% epicardium versus 21+/-4% endocardium). We also observed significant 3D diastolic dysfunction in the ischemic-reperfused region transmurally., Conclusions: Myocardial ischemia/reperfusion in the dog results in a significant transmural gradient of dysfunction between epicardial and endocardial layers in radial and cross-fiber segments, but not for fiber segments, despite a gradient in blood flow reduction during ischemia. Perhaps systolic fiber dysfunction rather than the degree of perfusion deficit during the preceding ischemic period may be the main determinant of myocardial dysfunction during reperfusion.

The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the ECG. Mutations in either of the two molecular components of the rapid delayed rectifier (I(K,r)), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I(K,r) density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel alpha subunits.

Objective: It is uncertain how reliably clinicians apply clinical predictors of group A beta hemolytic streptococcal pharyngitis (GABHSP) to form a clinical impression, and how reliably this impression predicts culture results. The objective was to study clinician accuracy in diagnosing GABHSP., Methods: This was a prospective cohort study, conducted at an urgent care center of a major university. A convenience sample of 218 patients, aged 9-83 years, presenting with sore throat, was enrolled. Symptoms and signs of pharyngitis were documented on a standardized form; the likelihood of GABHSP was plotted on a visual analog scale; and throat culture was obtained. A comparison was then made between the clinical impression on presentation and the throat culture result., Results: Throat cultures were positive for GABHSP in 41 patients (19%). The probability of GABHSP was related to node size and tenderness, tonsillar exudate and hypertrophy, and pharyngeal erythema (p<0.05); but not throat soreness, degree of fever, or cough. A strong clinical impression of GABHSP (>50% on the visual analog scale) was associated with tonsillar exudate and hypertrophy, tender nodes, and pharyngeal erythema. Together, these four predictors had a sensitivity of 71%, a specificity of 77%, and a positive predictive value of 46%., Conclusions: Clinicians in this study based their impression of GABHSP on the most reliable symptoms and signs. While a strong clinical suspicion of GABHSP predicted a greater probability of positive culture, the clinicians consistently overestimated the probability of GABHSP. Symptoms and signs predict GABHSP unreliably when used alone; they are helpful in modifying estimates of disease probability to facilitate optimal use of laboratory tests and antibiotics.

Myocardial ischemia and many other cardiac pathologies are associated with regional ventricular dysfunction. Since the distributions of stress and material properties cannot be measured directly in intact myocardium, understanding how regional alterations in myocardial strain or segment function are related to underlying cellular dysfunction must be deduced from theoretical models. Here, we describe how anatomically detailed, three-dimensional computational models can be used in conjunction with experimental or clinical studies to elucidate the structural basis of regional dysfunction in acutely ischemic and ischemic-reperfused ("stunned") myocardium in vivo. Integrative experimental and computational analysis shows that: (1) in acutely ischemic myocardium, the transition from abnormal systolic strain in the ischemic region to normal shortening in adjacent, normally perfused tissue is governed primarily by systolic blood pressure and regional fiber orientation rather than the geometry of the perfusion boundary; and (2) in stunned myocardium, the degree of reperfusion injury to the contractile apparatus may be uniform across the wall thickness despite observations that the extent of ischemia and the impairment of regional strain during reperfusion are both significantly greater in the subendocardium.

A new parametric model-based method has been developed that allows epicardial strain distributions to be computed on the left ventricular free wall in normal and ischemic myocardium and integrated with the regional distributions of anatomic and physiological measurements so that underlying relationships can be explored. An array of radiopaque markers was sewn on the anterior wall of the left ventricle (LV) in three anesthetized open-chest canines, and their positions were recorded using biplane video fluoroscopy before and 2 min after occlusion of the left anterior descending coronary artery. The three-dimensional (3D) anatomy of the LV and epicardial fiber angles were measured post-mortem using a 3D probe. A prolate spheroidal finite element model was fitted to the epicardial surface points (with <0.2 mm accuracy) and fiber angles (<5 degrees error). Regional myocardial blood flows (MBFs) were measured using fluorescent microspheres and fitted into the model (<0.3 ml min(-1) g(-1) error). Epicardial fiber and cross-fiber strain distributions were computed by allowing the model to deform from end-diastole to end-systole according to the recorded motion of the surface markers. Systolic fiber strain varied from -0.05 to 0.01 within the region of the markers during baseline, and regional MBF varied from 1.5 to 2.0 ml min(-1) g(-1). During 2 min ischemia, regional MBF was less than 0.3 ml min(-1) g(-1) in the ischemic region and 1.0 ml min(-1) g(-1) in the nonischemic region, and fiber strain ranged from 0.05 in the central ischemic zone to -0.025 in the remote nonischemic tissue. This analysis revealed a zone of impaired fiber shortening extending into the normally perfused myocardium that was significantly wider at the base than the apex. A validation analysis showed that a regularizing function can be optimized to minimize both fitting errors and numerical oscillations in the computed strain fields.