Understanding heterogeneous mechanisms of heart failure with preserved ejection fraction through cardiorenal mathematical modeling.

In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood pathophysiology. This study utilized mathematical modeling to evaluate mechanisms distinguishing HFpEF and HFrEF. HF was defined as a state of chronically elevated left ventricle end diastolic pressure (LVEDP > 20mmHg). First, using a previously developed cardiorenal model, sensitivities of LVEDP to potential contributing mechanisms of HFpEF, including increased myocardial, arterial, or venous stiffness, slowed ventricular relaxation, reduced LV contractility, hypertension, or reduced venous capacitance, were evaluated. Elevated LV stiffness was identified as the most sensitive factor. Large LV stiffness increases alone, or milder increases combined with either decreased LV contractility, increased arterial stiffness, or hypertension, could increase LVEDP into the HF range without reducing EF. We then evaluated effects of these mechanisms on mechanical signals of cardiac outward remodeling, and tested the ability to maintain stable EF (as opposed to progressive EF decline) under two remodeling assumptions: LV passive stress-driven vs. strain-driven remodeling. While elevated LV stiffness increased LVEDP and LV wall stress, it mitigated wall strain rise for a given LVEDP. This suggests that if LV strain drives outward remodeling, a stiffer myocardium will experience less strain and less outward dilatation when additional factors such as impaired contractility, hypertension, or arterial stiffening exacerbate LVEDP, allowing EF to remain normal even at high filling pressures. Thus, HFpEF heterogeneity may result from a range of different pathologic mechanisms occurring in an already stiffened myocardium. Together, these simulations further support LV stiffening as a critical mechanism contributing to elevated cardiac filling pressures; support LV passive strain as the outward dilatation signal; offer an explanation for HFpEF heterogeneity; and provide a mechanistic explanation distinguishing between HFpEF and HFrEF.

A 3-year analysis of the impact of COVID-19 pandemic on NSTEMI incidence, clinical characteristics, management, and outcomes.

OBJECTIVE: The COVID-19 pandemic has been associated with decreased incidence of acute coronary syndrome with worsened outcomes. Few studies have addressed the effects beyond the initial phases of the pandemic. This study elucidated the incidence, clinical characteristics, management, and outcomes of NSTEMI at a tertiary referral center from sample time periods of 2019-2022. METHODS: This study included consecutive NSTEMI patients from March 14-May 9, 2019-2022. Variables included baseline characteristics, clinical features on arrival, management strategy, time parameters, and adverse outcomes. The primary outcome was defined as death, heart failure requiring diuretics, and/or sustained ventricular arrhythmia. RESULTS: This study comprised 250 patients of whom 181 who were admitted during the COVID-19 outbreak. Baseline characteristics were similar among groups. There was a reduction in door-to-angiography time from 29 h in 2019 to 19 h in 2020 [p = 0.01] and 20 h in 2021 [p = 0.02]. PCI intervention increased from 31.8% in 2019% to 50.0% in 2020 [p = 0.05] and 54.7% in 2021 [p < 0.01]. Median length-of-stay (LOS) was reduced from 3 days in 2019 to 2 days in 2020 [p = 0.03]. There was no significant change in outcomes in COVID-19 cohorts compared to control year. CONCLUSIONS: NSTEMI patients during the first 2 years of the COVID-19 pandemic were associated with reduced door-to-angiography times and increased percutaneous coronary intervention (PCI), and patients in year one were associated with reduced LOS. This study suggests that NSTEMI may be managed more efficiently thus reducing hospital bed utilization and potential costs.

Effect of mineralocorticoid receptor antagonists on cardiac function in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

Heart failure with preserved ejection fraction (HFpEF) is a disease with limited evidence-based treatment options. Mineralocorticoid receptor antagonists (MRA) offer benefit in heart failure with reduced ejection fraction (HFrEF), but their impact in HFpEF remains unclear. We therefore evaluated the effect of MRA on echocardiographic, functional, and systemic parameters in patients with HFpEF by a systematic review and meta-analysis. We searched MEDLINE, EMBASE, clinicaltrials.gov , and Cochrane Clinical Trial Collection to identify randomized controlled trials that (a) compared MRA versus placebo/control in patients with HFpEF and (b) reported echocardiographic, functional, and/or systemic parameters relevant to HFpEF. Studies were excluded if: they enrolled asymptomatic patients; patients with HFrEF; patients after an acute coronary event; compared MRA to another active comparator; or reported a follow-up of less than 6 months. Primary outcomes were changes in echocardiographic parameters. Secondary end-points were changes in functional capacity, quality of life measures, and systemic parameters. Quantitative analysis was performed by generating forest plots and calculating effect sizes by random-effect models. Between-study heterogeneity was assessed through Q and I2 statistics. Nine trials with 1164 patients were included. MRA significantly decreased E/e' (mean difference - 1.37, 95% confidence interval - 1.72 to - 1.02), E/A (- 0.04, - 0.08 to 0.00), left ventricular end-diastolic diameter (- 0.78 mm, - 1.34 to - 0.22), left atrial volume index (- 1.12 ml/m2, - 1.91 to - 0.33), 6-min walk test distance (- 11.56 m, - 21 to - 2.13), systolic (- 4.75 mmHg, - 8.94 to - 0.56) and diastolic blood pressure (- 2.91 mmHg, - 4.15 to - 1.67), and increased levels of serum potassium (0.23 mmol/L, 0.19 to 0.28) when compared with placebo/control. In patients with HFpEF, MRA treatment significantly improves indices of cardiac structure and function, suggesting a decrease in left ventricular filling pressure and reverse cardiac remodeling. MRA increase serum potassium and decrease blood pressure; however, a small decrease in 6-min-walk distance is also noted. Larger prospective studies are warranted to provide definitive answers on the effect of MRA in patients with HFpEF.

Effect of exercise intensity on circulating microparticles in men and women.

NEW FINDINGS: What is the central question of this study? What is the effect of exercise intensity on circulating microparticle populations in young, healthy men and women? What is the main finding and its importance? Acute, moderate-intensity continuous exercise and high-intensity interval exercise altered distinct microparticle populations during and after exercise in addition to a sex-specific response in CD62E+ microparticles. The microparticles studied contribute to cardiovascular disease progression, regulate vascular function and facilitate new blood vessel formation. Thus, characterizing the impact of intensity on exercise-induced microparticle responses advances our understanding of potential mechanisms underlying the beneficial vascular adaptations to exercise. ABSTRACT: Circulating microparticles (MPs) are biological vectors of information within the cardiovascular system that elicit both deleterious and beneficial effects on the vasculature. Acute exercise has been shown to alter MP concentrations, probably through a shear stress-dependent mechanism, but evidence is limited. Therefore, we investigated the effect of exercise intensity on plasma levels of CD34+ and CD62E+ MPs in young, healthy men and women. Blood samples were collected before, during and after two energy-matched bouts of acute treadmill exercise: interval exercise (10 × 1 min intervals at ∼95% of maximal oxygen uptake V̇O2max) and continuous exercise (65% V̇O2max). Continuous exercise, but not interval exercise, reduced CD62E+ MP concentrations in men and women by 18% immediately after exercise (from 914.5 ± 589.6 to 754.4 ± 390.5 MPs µl-1 ; P < 0.05), suggesting that mechanisms underlying exercise-induced CD62E+ MP dynamics are intensity dependent. Furthermore, continuous exercise reduced CD62E+ MPs in women by 19% (from 1030.6 ± 688.1 to 829.9 ± 435.4 MPs µl-1 ; P < 0.05), but not in men. Although interval exercise did not alter CD62E+ MPs per se, the concentrations after interval exercise were higher than those observed after continuous exercise (P < 0.05). Conversely, CD34+ MPs did not fluctuate in response to short-duration acute continuous or interval exercise in men or women. Our results suggest that exercise-induced MP alterations are intensity dependent and sex specific and impact MP populations differentially.

Differences in vascular nitric oxide and endothelium-derived hyperpolarizing factor bioavailability in blacks and whites.

OBJECTIVE: Abnormalities in nitric oxide (NO) bioavailability have been reported in blacks. Whether there are differences in endothelium-derived hyperpolarizing factor (EDHF) in addition to NO between blacks and whites and how these affect physiological vasodilation remain unknown. We hypothesized that the bioavailability of vascular NO and EDHF, at rest and with pharmacological and physiological vasodilation, varies between whites and blacks. APPROACH AND RESULTS: In 74 white and 86 black subjects without known cardiovascular disease risk factors, forearm blood flow was measured using plethysmography at rest and during inhibition of NO with N(G)-monomethyl-L-arginine and of K(+) Ca channels (EDHF) with tetraethylammonium. The reduction in resting forearm blood flow was greater with N(G)-monomethyl-L-arginine (P=0.019) and similar with tetraethylammonium in whites compared with blacks. Vasodilation with bradykinin, acetylcholine, and sodium nitroprusside was lower in blacks compared with whites (all P<0.0001). Inhibition with N(G)-monomethyl-L-arginine was greater in whites compared with blacks with bradykinin, acetylcholine, and exercise. Inhibition with tetraethylammonium was lower in blacks with bradykinin, but greater during exercise and with acetylcholine. CONCLUSIONS: The contribution to both resting and stimulus-mediated vasodilator tone of NO is greater in whites compared with blacks. EDHF partly compensates for the reduced NO release in exercise and acetylcholine-mediated vasodilation in blacks. Preserved EDHF but reduced NO bioavailability and sensitivity characterizes the vasculature in healthy blacks. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/. Unique identifier: NCT00166166.

Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia.

The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. CLINICAL TRIAL REGISTRATION IDENTIFIER NCT00166166:

Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans.

AIMS: Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. METHODS: In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 µmol/min), fluconazole (0.4 µmol·min(-1)·l(-1)), and N(G)-monomethyl-L-arginine (L-NMMA, 8 µmol/min) to block nitric oxide, and their combination in separate studies. RESULTS: BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). CONCLUSION: BK-stimulated t-PA release is partly due to cytochrome P450-derived epoxides and is inhibited by K(+)Ca channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.

Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial.

IMPORTANCE: Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE: To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS: Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 µg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES: The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS: Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE: Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01041417.

Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease.

BACKGROUND: We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit K(+)(Ca) channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by K(+)(Ca) channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. METHODS AND RESULTS: In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N(G)-monomethyl-l-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K(+)(Ca) channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04). CONCLUSIONS: First, by activating TEA-inhibitable K(+)(Ca) channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of K(+)(Ca) channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of K(+)(Ca) channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates K(+)(Ca) channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K(+)(Ca) channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00166166.

Reducing costs and improving care after hospitalization: Economic evaluation of a novel transitional care clinic.

Transitional care management (TCM) is a novel strategy for reducing costs and improving clinical outcomes after hospitalization but remains under-utilized. An economic analysis was performed on a hospital-based transition of care clinic (TCC) open to all patients regardless of payor status. TCC reduced re-hospitalization and emergency department (ED) utilization at six-month follow up. A cost-consequence analysis based on real world data found the TCC intervention to be cost effective relative to usual care. Hospital managers should consider adoption of TCC to improve patient care and reduce costs.

CD34(+) cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent.

BACKGROUND: the objective of the study was to determine whether the effects of infarct-related artery (IRA) infusion of autologous bone marrow-derived CD34(+) cells after ST elevation myocardial infarction (STEMI) are dependent on the dose (quantity and mobility) of the cells infused. Beneficial effects of IRA infusion of mononuclear cells after STEMI have been inconsistent, possibly because of differences in timing, cell type, quantity, and mobility of infused cells. METHODS: patients were randomized to bone marrow harvest (n = 16) or control (n = 15). At a median of 8.3 days after coronary stenting for STEMI, CD34(+) cells were infused via the IRA at 3 dose levels (5, 10, and 15 × 10(6)) in cohorts of 5 patients each. Baseline and follow-up imaging and ex vivo CD34(+) cell mobility were performed. RESULTS: Cell harvest and infusion were safe. Quantitative rest hypoperfusion score measured by single-photon emission computed tomography improved at 6 months in the ≥ 10 million cohorts compared with controls (-256 vs +14, P = .02). There was a trend toward improved ejection fraction at 6 months (+4.5%) in the ≥ 10 million cohorts compared with no change in the controls and 5 million cohort (+0.7%). Improved perfusion and infarct size reduction correlated with the quantity and mobility of the infused CD34(+) cells. CONCLUSIONS: the effects of CD34(+) cell IRA infusion during the repair phase after STEMI are dose dependent and, at a threshold dose of 10 million CD34(+) cells, associated with a significant improvement in perfusion that may limit deterioration in cardiac function (IRA infusion of CD34(+) cells in patients with acute myocardial infarction [AMR-01] NCT00313339).

Characterization of mechanical dyssynchrony measured by gated single photon emission computed tomography phase analysis after acute ST-elevation myocardial infarction.

BACKGROUND: Left ventricular dyssynchrony is an adverse consequence of ST-elevation myocardial infarction (STEMI) and bears an unfavorable prognosis. Mechanical dyssynchrony as measured by phase analysis from gated single photon emission computed tomography (GSPECT) correlates well with other imaging methods of assessing dyssynchrony but has not been studied in STEMI. We hypothesized that systolic dyssynchrony as measured by GSPECT would correlate with adverse remodeling after STEMI. METHODS: In 28 subjects suffering STEMI, GSPECT with technetium-99m sestamibi was performed immediately after presentation (day 5) and remotely (6 months). Parameters of left ventricular dyssynchrony (QRS width, histogram bandwidth (HBW) and phase standard deviation (PSD)) were measured from GSPECT using the Emory Cardiac Toolbox. Left ventricular volumes, ejection fraction (LVEF) and infarct size were also assessed. RESULTS: After successful primary percutaneous coronary intervention to the infarct-related artery, subjects had an LVEF of 46.4% ± 11% and a resting perfusion defect of 27.4% ± 16% at baseline. Baseline QRS width was normal (91.5 ± 17.5 ms). Subjects with STEMI had dyssynchrony compared with a cohort of 22 normal subjects (age 57.2 ± 10.6 years, <5% perfusion defect) by both HBW (100.3° ± 70.7° vs 26.5° ± 5.3°, P < .0001) and PSD (35.3° ± 16.9° vs 7.9° ± 2.1°, P < .0001). Baseline HBW correlated with resting perfusion defect size (r = 0.67, P < .001), end-systolic volume (r = 0.72, P < .001), end-diastolic volume (r = 0.63, P = .001), and inversely with LVEF (r = -0.74, P < .001). HBW and PSD improved over the follow-up period (-24.1 ± 35.9 degrees, P = .003 and -8.7° ± 14.6°, P = .006, respectively), and improvement in HBW correlated with reduction in LV end-systolic volumes (r = 0.43, P = .034). Baseline HBW and PSD, however, did not independently predict LVEF at 6 months follow-up. CONCLUSIONS: After STEMI, subjects exhibit mechanical dyssynchrony as measured by GSPECT phase analysis without evidence of electrical dyssynchrony. Improvement in mechanical dyssynchrony correlates with beneficial ventricular remodeling. The full predictive value of this measure in post-infarct patients warrants further study.

Fundamentals of integrated ferrohydrodynamic cell separation in circulating tumor cell isolation.

Methods to separate circulating tumor cells (CTCs) from blood samples were intensively researched in order to understand the metastatic process and develop corresponding clinical assays. However current methods faced challenges that stemmed from CTCs' heterogeneity in their biological markers and physical morphologies. To this end, we developed integrated ferrohydrodynamic cell separation (iFCS), a scheme that separated CTCs independent of their surface antigen expression and physical characteristics. iFCS integrated both diamagnetophoresis of CTCs and magnetophoresis of blood cells together via a magnetic liquid medium, ferrofluid, whose magnetization could be tuned by adjusting its magnetic volume concentration. In this paper, we presented the fundamental theory of iFCS and its specific application in CTC separation. Governing equations of iFCS were developed to guide its optimization process. Three critical parameters that affected iFCS's cell separation performance were determined and validated theoretically and experimentally. These parameters included the sample flow rate, the volumetric concentration of magnetic materials in the ferrofluid, and the gradient of the magnetic flux density. We determined these optimized parameters in an iFCS device that led to a high recovery CTC separation in both spiked and clinical samples.

Bone marrow mobilization with granulocyte macrophage colony-stimulating factor improves endothelial dysfunction and exercise capacity in patients with peripheral arterial disease.

BACKGROUND: We hypothesized that granulocyte macrophage colony-stimulating factor (GM-CSF) administration will be safe and will improve endothelial dysfunction and exercise capacity by mobilizing progenitor cells in patients with peripheral arterial disease (PAD). METHODS: Forty-five patients with PAD received thrice-weekly injections for 2 weeks of 3, 6, or 10 microg/kg per day of GM-CSF or placebo in successive cohorts of 15 subjects randomized 2:1 to drug or placebo. CD34+ mononuclear cell subsets and colony formation assay, endothelial function, ankle-brachial index, and walking capacity were measured. RESULTS: Granulocyte macrophage colony-stimulating factor administration was safe. After pooling data from GM-CSF cohorts, at 2 weeks, there was a significant increase in total leukocytes (43%, P < .0001), CD34+ cells (46%, P = .035), and colony-forming units (31%, P = .026, week 1). At 12 weeks, endothelial function improved with GM-CSF (flow-mediated vasodilation increased by 59%, P < .01) as did pain-free treadmill walking time (38 seconds, P = .008) and total treadmill walking time (55 seconds, P = .016). Corresponding changes were not observed in the placebo group. CONCLUSIONS: Granulocyte macrophage colony-stimulating factor therapy in patients with PAD was associated with mobilization of progenitor cells, improvement of endothelial dysfunction, and exercise capacity. The efficacy of strategies designed to mobilize bone marrow progenitors warrants further study in patients with PAD.

Exploring magnetohydrodynamic voltage distributions in the human body: Preliminary results.

BACKGROUND: The aim of this study was to noninvasively measure regional contributions of vasculature in the human body using magnetohydrodynamic voltages (VMHD) obtained from electrocardiogram (ECG) recordings performed inside MRI's static magnetic field (B0). Integrating the regional VMHD over the Swave-Twave segment of the cardiac cycle (Vsegment) provides a non-invasive method for measuring regional blood volumes, which can be rapidly obtained during MRI without incurring additional cost. METHODS: VMHD was extracted from 12-lead ECG traces acquired during gradual introduction into a 3T MRI. Regional contributions were computed utilizing weights based on B0's strength at specified distances from isocenter. Vsegment mapping was performed in six subjects and validated against MR angiograms (MRA). RESULTS: Fluctuations in Vsegment, which presented as positive trace deflections, were found to be associated with aortic-arch flow in the thoracic cavity, the main branches of the abdominal aorta, and the bifurcation of the common iliac artery. The largest fluctuation corresponded to the location where the aortic arch was approximately orthogonal to B0. The smallest fluctuations corresponded to areas of vasculature that were parallel to B0. Significant correlations (specifically, Spearman's ranked correlation coefficients of 0.96 and 0.97 for abdominal and thoracic cavities, respectively) were found between the MRA and Vsegment maps (p < 0.001). CONCLUSIONS: A novel non-invasive method to extract regional blood volumes from ECGs was developed and shown to be a rapid means to quantify peripheral and abdominal blood volumes.

Near infrared spectroscopy-guided exercise training for claudication in peripheral arterial disease.

RATIONALE: Supervised treadmill exercise for claudication in peripheral arterial disease is effective but poorly tolerated because of ischemic leg pain. Near infrared spectroscopy allows non-invasive detection of muscle ischemia during exercise, allowing for characterization of tissue perfusion and oxygen utilization during training. OBJECTIVE: We evaluated walking time, muscle blood flow, and muscle mitochondrial capacity in patients with peripheral artery disease after a traditional pain-based walking program and after a muscle oxygen-guided walking program. METHOD AND RESULTS: Patients with peripheral artery disease trained thrice weekly in 40-minute-long sessions for 12 weeks, randomized to oxygen-guided training ( n = 8, age 72 ± 9.7 years, 25% female) versus traditional pain-based training ( n = 10, age 71.6 ± 8.8 years, 20% female). Oxygen-guided training intensity was determined by maintaining a 15% reduction in skeletal muscle oxygenation by near infrared spectroscopy rather than relying on symptoms of pain to determine exercise effort. Pain free and maximal walking times were measured with a 12-minute Gardner treadmill test. Gastrocnemius mitochondrial capacity and blood flow were measured using near infrared spectroscopy. Baseline pain-free walking time was similar on a Gardner treadmill test (2.5 ± 0.9 vs. 3.6 ± 1.0 min, p = 0.5). After training, oxygen-guided cohorts improved similar to pain-guided cohorts (pain-free walking time 6.7 ± 0.9 vs. 6.9 ± 1.1 min, p < 0.01 for change from baseline and p = 0.97 between cohorts). Mitochondrial capacity improved in both groups but more so in the pain-guided cohort than in the oxygen-guided cohort (38.8 ± 8.3 vs. 14.0 ± 9.3, p = 0.018). Resting muscle blood flow did not improve significantly in either group with training. CONCLUSIONS: Oxygen-guided exercise training improves claudication comparable to pain-based training regimens. Adaptations in mitochondrial function rather than increases in limb perfusion may account for functional improvement. Increases in mitochondrial oxidative capacity may be proportional to the degree of tissue hypoxia during exercise.

Tumor antigen-independent and cell size variation-inclusive enrichment of viable circulating tumor cells.

Isolation of circulating tumor cells (CTCs) from blood provides a minimally-invasive alternative for basic understanding, diagnosis, and prognosis of metastatic cancer. The roles and clinical values of CTCs are under intensive investigation, yet most studies are limited by technical challenges in the comprehensive enrichment of intact and viable CTCs with minimal white blood cell (WBC) contamination. Here, we report a novel method based on contrast of cell magnetization in biocompatible ferrofluids (a colloidal magnetic nanoparticle suspension), termed as integrated ferrohydrodynamic cell separation (iFCS), that enriches CTCs in a tumor antigen-independent and cell size variation-inclusive manner, achieves a high throughput (12 mL h-1), high recovery rate (99.08% at down to ∼10 cells per mL spike ratio), and low WBC contamination (533 cells for every one milliliter blood processed) and is biocompatible. This method will enable large cohort research to define the clinical and diagnostic value of CTC subtypes.

Magnetohydrodynamic Voltage Recorder for Comparing Peripheral Blood Flow.

Blood flow is a clinical metric for monitoring of cardiovascular diseases but current measurements methods are costly or uncomfortable for patients. It was shown that the interaction of the magnetic field (B 0) during MRI and blood flow in the body, through the magnetohydrodynamic (MHD) effect, produce voltages (V MHD) observable through intra-MRI electrocardiography (ECG), which are correlated with regional blood flow. This study shows the reproducibility of V MHD outside the MRI and its application in a portable flow monitoring device. To recreate this interaction outside the MRI, a static neodymium magnet (0.4T) was placed in between two electrodes to induce the V MHD in a single lead ECG measurement. V MHD was extracted, and integrated over to obtain a stroke volume metric. A smartphone-enabled device utilizing this interaction was developed in order to create a more accessible method of obtaining blood flow measurements. The portable device displayed a <6% error compared to a commercial recorder, and was able to successfully record V MHD using the 0.4T magnet. Exercise stress testing showed a V MHD increase of 23% in healthy subjects, with an 81% increase in the athlete. The study demonstrates a new device utilizing MHD interactions with body circulation to obtain blood flow metrics.