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Background: Acute cellular rejection (ACR), an alloimmune response involving CD4+ and CD8+ T cells, occurs in up to 20% of patients within the first year following heart transplantation. The balance between a conventional versus regulatory CD4+ T cell alloimmune response is believed to contribute to developing ACR. Therefore, tracking these cells may elucidate whether changes in these cell populations could signal ACR risk., Methods: We used a CD4+ T cell gene signature (TGS) panel that tracks CD4+ conventional T cells (Tconv) and regulatory T cells (Treg) on longitudinal samples from 94 adult heart transplant recipients. We evaluated combined diagnostic performance of the TGS panel with a previously developed biomarker panel for ACR diagnosis, HEARTBiT, while also investigating TGS' prognostic utility., Results: Compared with nonrejection samples, rejection samples showed decreased Treg- and increased Tconv-gene expression. The TGS panel was able to discriminate between ACR and nonrejection samples and, when combined with HEARTBiT, showed improved specificity compared with either model alone. Furthermore, the increased risk of ACR in the TGS model was associated with lower expression of Treg genes in patients who later developed ACR. Reduced Treg gene expression was positively associated with younger recipient age and higher intrapatient tacrolimus variability., Conclusions: We demonstrated that expression of genes associated with CD4+ Tconv and Treg could identify patients at risk of ACR. In our post hoc analysis, complementing HEARTBiT with TGS resulted in an improved classification of ACR. Our study suggests that HEARTBiT and TGS may serve as useful tools for further research and test development., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Whether viability imaging can impact long-term patient outcomes is uncertain. The PARR-2 study (Positron Emission Tomography and Recovery Following Revascularization) showed a nonsignificant trend toward improved outcomes at 1 year using an F-18-fluorodeoxyglucose positron emission tomography (PET)-assisted strategy in patients with suspected ischemic cardiomyopathy. When patients adhered to F-18-fluorodeoxyglucose PET recommendations, outcome benefit was observed. Long-term outcomes of viability imaging-assisted management have not previously been evaluated in a randomized controlled trial., Methods and Results: PARR-2 randomized patients with severe left ventricular dysfunction and suspected CAD being considered for revascularization or transplantation to standard care (n= 195) versus PET-assisted management (n=197) at sites participating in long-term follow-up. The predefined primary outcome was time to composite event (cardiac death, myocardial infarction, or cardiac hospitalization). After 5 years, 105 (53%) patients in the PET arm and 111 (57%) in the standard care arm experienced the composite event (hazard ratio for time to composite event =0.82 [95% confidence interval 0.62-1.07]; P=0.15). When only patients who adhered to PET recommendations were included, the hazard ratio for the time to primary outcome was 0.73 (95% confidence interval 0.54-0.99; P=0.042)., Conclusions: After a 5-year follow-up in patients with left ventricular dysfunction and suspected CAD, overall, PET-assisted management did not significantly reduce cardiac events compared with standard care. However, significant benefits were observed when there was adherence to PET recommendations. PET viability imaging may be best applied when there is likely to be adherence to imaging-based recommendations., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00385242., (© 2016 American Heart Association, Inc.)

Background: There remains limited insight into the pathophysiology and therapeutic advances directed at improving prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive, quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health. The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial coronary artery disease., Methods and Results: A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure (n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69 in HFpEF versus 2.54±0.80 in hypertensive controls; P<0.02 and 2.89±0.70 in normotensive controls; P<0.001). A diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities., Conclusions: HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is associated with reduced MFR independent of other risk factors., (© 2016 American Heart Association, Inc.)

Background: Cardiac allograft vasculopathy is a key prognostic determinant after heart transplant. Detection and risk stratification of patients with cardiac allograft vasculopathy are problematic. Positron emission tomography using rubidium-82 allows quantification of absolute myocardial blood flow and may have utility for risk stratification in this population., Methods and Results: Patients with a history of heart transplant undergoing dipyridamole rubidium-82 positron emission tomography were prospectively enrolled. Myocardial perfusion and left ventricular ejection fraction were recorded. Absolute flow quantification at rest and after dipyridamole stress as well as the ratio of mean global flow at stress and at rest, termed myocardial flow reserve, were calculated. Patients were followed for all-cause death, acute coronary syndrome, and heart failure hospitalization. A total of 140 patients (81% men; median age, 62 years; median follow-up, 18.2 months) were included. There were 14 events during follow-up (9 deaths, 1 acute coronary syndrome, and 4 heart failure admissions). In addition to baseline clinical variables (estimated glomerular filtration rate, previously documented cardiac allograft vasculopathy), relative perfusion defects, mean myocardial flow reserve, and mean stress myocardial blood flow were significant predictors of adverse outcome., Conclusions: Abnormalities on rubidium-82 positron emission tomography were predictors of adverse events in heart transplant patients. Larger prospective studies are required to confirm these findings., (© 2014 American Heart Association, Inc.)

Background: Left heart failure is characterized by alterations in metabolic substrate utilization, and metabolic modulation may be a future strategy in the management of heart failure. Little is known about cardiac metabolism in the right ventricle and how it relates to other measures of right ventricular (RV) function. This study was designed to measure glucose metabolism in the right ventricle, as estimated by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography imaging and to determine the relation between RV function and FDG uptake in patients with heart failure., Methods and Results: A total of 68 patients underwent cardiac [(18)F]FDG positron emission tomography scanning with measurement of RV FDG uptake as a standardized uptake value. Perfusion imaging was acquired at rest with rubidium-82 or [(13)N]ammonia. RV function was determined by equilibrium radionuclide ventriculography. Relative RV FDG uptake was determined as the ratio of RV to LV standardized uptake value. Fifty-five percent of these patients had ischemic cardiomyopathy. The mean LV and RV ejection fractions were 21±7% and 35±10%, respectively. There was a correlation between RV ejection fraction and the ratio of RV to LV FDG uptake whether the entire LV myocardium (r=-0.40, P<0.001) or LV free wall (r=-0.43, P<0.001) was used. This relation persisted in the subgroup with nonischemic cardiomyopathy (r=-0.37, P=0.04). RV FDG uptake was weakly related to increased RV systolic pressure but not related to LV size, function, or FDG uptake. The correlation between RV ejection fraction and RV/LV FDG was maintained after partial-volume correction (r=-0.68, P<0.001)., Conclusions: RV dysfunction is associated with an increase in RV FDG uptake, the magnitude of which may be correlated with severity.

Heterozygous PAX6 mutation is associated with an absent or hypoplastic anterior commissure and a reduction in the area of the corpus callosum. The authors found deficient auditory interhemispheric transfer in a 53-year-old woman with a PAX6 mutation who had an absent anterior commissure but normal callosal volume.

Aims: To study the effect of long-term exposure to global system for mobile communication (GSM) radiofrequency fields on vascular permeability in murine brains., Methods: Using a purpose-designed exposure system at 900 MHz, mice were given a 60-minute far-field, whole body exposure on each of 5 days per week for 104 weeks at specific absorption rates (SAR) of 0.25, 1.0,2.0 and 4.0 W/kg. Control mice were sham-exposed or permitted free movement in a cage to evaluate any stress-related effects. Albumin immunohistochemistry was used to detect increased vascular permeability and the efficacy of the vascular tracer was confirmed with a positive control group exposed to a clostridial toxin known to increase vascular permeability in the brain., Results: In all exposed and control groups, albumin extravasation was minimal, often leptomeningeal, and was deemed insignificant as a maximum of three capillaries or venules in a given brain showed leakage from the very many blood vessels present in the three coronal brain sections., Conclusions: These results suggest that prolonged exposure to mobile telephone-type radiation produces negligible disruption to blood-brain barrier integrity at the light microscope level using endogenous albumin as a vascular tracer.

Objective: We compared the treatment outcome of patients with benign paroxysmal positional vertigo unassociated with additional objective evidence of vestibular pathology (BPPV) with that in patients who did demonstrate additional vestibular pathology on standard neurotologic testing (BPPV+)., Study Design: An open, retrospective, record-based study., Setting: Specialized outpatient dizziness clinic., Patients and Methods: We reviewed 58 unselected patients with a Dix-Hallpike test demonstrating positioning nystagmus characteristic of BPPV, who were treated during the past 4 years with the particle repositioning maneuver. Before treatment, all patients underwent detailed clinical and laboratory neurotological testing., Main Outcome Measures: The treatment outcome was assessed with regard to persistence of symptoms and the presence of positioning nystagmus on Dix-Hallpike testing., Results: Seventy-eight percent of patients with BPPV no longer demonstrated characteristic positional nystagmus after 1 particle repositioning maneuver compared with 71% of patients with BPPV+ (p = 0.56) who did, whereas 13% of the BPPV and 14% of the BPPV+ group required more than 1 treatment to be rendered nystagmus negative on Dix-Hallpike testing (p = 0.89). However, 14% of patients with BPPV remained dizzy, compared with 63% patients from the BPPV+ group, despite a negative Dix-Hallpike test after treatment (p = 0.0018). Patients with horizontal canal paresis (n = 15) had a better outcome than patients with central vestibular dysfunction (n = 7, p = 0.006). Etiologic factors seemed to affect outcome-patients with idiopathic BPPV and those with a preceding acute vestibular neuronitis had a tendency for a better outcome than BPPV patients with any other etiology (p = 0.058)., Conclusion: Our study demonstrates that patients with BPPV+ do not have a worse prognosis with respect to resolution of positional nystagmus, on performing the particle repositioning procedure, compared with patients with uncomplicated BPPV. However, they do suffer incomplete resolution of symptoms because of a coincidental anterior or horizontal canal dysfunction and otolithic or central vestibular dysfunction. It appears that the majority of patients with BPPV+ need further vestibular rehabilitation after the particle repositioning maneuver.

Background: Increased circulating levels of the cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) may be observed after orthotopic cardiac transplantation. Both the hypertrophic and inflammatory processes in the allograft may contribute to this increase, but no mechanistic explanation has been suggested for this observation., Methods and Results: Plasma immunoreactive ANF and BNP determinations were performed in 10 consecutive transplant patients. These were correlated with degree of rejection as reflected by histopathological findings at serial endomyocardial biopsies. Three patients had associated hemodynamic measurements and blood samples 24 hours before and after transplantation. All rejection episodes that received treatment were accompanied by a marked increase in BNP plasma levels to > approximately 400 pg/mL. Steadily increasing BNP levels preceded overt rejection as assessed by histopathological criteria. The increase in plasma BNP was not always accompanied by an increase in ANF, which suggests the specific upregulation of BNP gene expression during acute rejection episodes. Treatment of the acute rejection episodes led to a substantial decrease of BNP plasma levels., Conclusions: The significant selective increase in plasma BNP levels found in the present study has not been previously described. This finding provides a new insight into the mechanism of allograft rejection and the modulation of natriuretic peptide synthesis and release. Furthermore, although preliminary, the data suggest that BNP plasma levels could form the basis for a new, noninvasive screening test to predict acute cardiac allograft rejection. Because treatment with the antilymphocyte monoclonal antibody OKT3 (murine monoclonal antibody to the CD3 antigen of the human T-cell) decreased BNP plasma levels, cytokine production by T-cells may mediate the selective increase in circulating BNP.

Background: In healthy human hearts, beta 2-receptor-mediated chronotropic and inotropic responses contribute to the cardiac responses to beta-agonists. A (patho)physiological relevance for beta 2-receptor-mediated responses has so far not been demonstrated, in part because beta 1-receptor-mediated responses to cardiac neuronally released norepinephrine can mask beta 2-receptor-mediated responses., Methods and Results: In the present study, we evaluated the blood pressure and heart rate responses to bicycle exercise in cardiac transplant patients (n = 7) compared with patients with essential hypertension (n = 8) on placebo and two doses of the beta 1-selective beta-blocker atenolol (25 and 50 mg/d) and the nonselective beta-blocker nadolol (20 and 40 mg/d), each dose for 1 week using a double-blind, randomized, crossover design. Exercise was performed 3 hours after dosing, using a stepwise increase in load until exhaustion. Exercise performance was less in the transplant patients and significantly further (25%) decreased by nadolol. Exercise caused equivalent increases in plasma norepinephrine in the two groups, but more marked increases in plasma epinephrine in the transplant patients despite less exercise. In the essential hypertension patients, systolic blood pressure increased by 80 mm Hg on placebo and 60 mm Hg on either blocker. The increase in heart rate (by about 75 beats per minute) was inhibited by 10% and 20% by the lower and higher doses, respectively, similar for the two blockers. In contrast, in the transplant patients, systolic blood pressure increased by 60 mm Hg on placebo, but this increase was totally blocked by either blocker. The heart rate increase (by 50 beats per minute on placebo) was blunted (dose related) by either blocker but 50% more by nadolol versus atenolol., Conclusions: The present study shows that cardiac beta 2-receptors contribute to a clear extent to the heart rate responses to endogenous circulating catecholamines in the absence of cardiac neuronally released norepinephrine. Nonselective beta-blockade probably is less well tolerated in cardiac transplant patients compared with beta 1-selective blockade.

Background: Accelerated allograft atherosclerosis is the main cause of death of cardiac transplant recipients after the first year after transplantation. Because no medical therapy is known to prevent or retard graft atherosclerosis and transplantation is associated with a shortened allograft survival, alternative, palliative therapy with percutaneous transluminal coronary angioplasty (PTCA) has been attempted. Because no single medical center has performed angioplasty in a large number of cardiac transplant recipients, representatives of 11 medical centers retrospectively analyzed their complete experience of coronary angioplasty in cardiac transplant patients to determine the safety, efficacy, limitations, and long-term outcome of angioplasty in allograft coronary vascular disease., Methods and Results: Thirty-five patients underwent 51 angioplasty procedures for 95 lesions 46 +/- 5 months (mean +/- SEM) after transplantation. The primary indications for angioplasty included angiographic coronary disease in 22 cases (43%) and noninvasive evidence of ischemia in 18 procedures (35%). Angiographic success, defined as less than or equal to 50% post-PTCA stenosis, occurred in 88 of 95 lesions (93%). Mean pre-PTCA stenosis was 83 +/- 1.1%; mean post-PTCA stenosis was 29 +/- 2.1% (p less than 0.0001). Periprocedural complications included myocardial infarction and late in-hospital death in one patient and three groin hematomas. Twenty-three of the 35 patients (66%) had no major adverse outcome such as death, retransplantation, or myocardial infarction at 13 +/- 3 months after angioplasty. Four patients died less than 6 months after angioplasty, and four died more than 6 months after angioplasty (range, 6-23 months). Two patients had retransplantation 2 months after PTCA, and one patients had retransplantation 18 months after angioplasty., Conclusions: Coronary angioplasty may be applied in selected cardiac transplant recipients with comparable success and complication rates to routine angioplasty. Whether angioplasty prolongs allografts survival remains to be determined by a prospective, controlled trial.

The right ventricular (RV) response to upright bicycle exercise was assessed in 16 patients with chronic obstructive pulmonary disease (COPD), in 23 patients with coronary artery disease (CAD), and in 19 normal control subjects. Right ventricular (RV) and left ventricular (LV) ejection fractions were determined noninvasively using first-pass quantitative radionuclide angiocardiography, a technique well suited for simultaneous assessment of RV and LV systolic performance. The factors limiting exercise in COPD and CAD are distinctly different, and therefore patients with COPD were studied by means of a single-stage submaximal exercise test, while patients with CAD were studied by means of a graded maximal test. The normal response to exercise, irrespective of exercise protocol, was at least a 5% increase in RV and LV ejection fractions. In 12 of 16 patients with COPD, RV ejection fraction either decreased or remained the same with exercise (abnormal exercise RV reserve). Left ventricular exercise reserve was abnormal only in five patients, probably due to occult CAD. Isolated abnormal exercise RV reserve was present in nine patients. The severity of ventilatory impairment and resting arterial hypoxemia were major determinants of abnormal exercise RV reserve in patients with COPD. In 12 or 23 patients with CAD, RV ejection fraction either decreased or remained the same with exercise (abnormal exercise RV reserve). Left ventricular reserve was abnormal in 18 of 23 patients; RV exercise reserve was abnormal only in CAD patients with concomitant abnormal LV reserve. The presence of proximal right coronary artery stenosis (the major blood supply to the RV) was not a significant determinant of the RV response to exercise in patients with CAD. These data suggest that abnormal exercise RV reserve occurs frequently both in COPD and CAD patients. In COPD the predominant hemodynamic abnormality involves performance of the RV, while in CAD the predominant abnormality involves the LV. The common factor modulating RV exercise performance in both diseases appears to be altered RV afterload.

The feasibility, accuracy and reproducibility of continuous beat-to-beat evaluation of left ventricular performance with a computerized nonimaging scintillation probe was assessed in 71 patients. This portable instrument has enough sensitivity to generate a real-time relative left ventricular volume curve using the labeled equilibrium blood pool without electrocardiographic gating. The probe was positioned at the left ventricular and background regions of interest using a systematic series of computerized algorithms and operator routines that were developed and standardized during the initial phase of this study. In each patient, left ventricular ejection fraction was calculated manually from the strip-chart recording in 10 consecutive sinus beats. Beat-to-beat left ventricular ejection fraction determined by the probe correlated well with first-pass studies obtained using a computerized multicrystal scintillation camera (r = 0.92). There was no systematic over- or underestimation, and the correlation was evident over a wide range of first-pass values (15-81%). There was excellent agreement between initial and repeat analyses (n = 58, r = 0.97) and between initial and repeat studies (n = 48, r = 0.94). The absolute variability of beat-to-beat ejection fraction measurements determined from all 710 beats was +/- 5.9% (expressed in ejection fraction units as +/- 2 SD). This technique should provide a reliable means of addressing pathophysiologic questions that require sampling of data directly on a beat-to-beat basis.

The feasibility of imaging the inflammatory response to acute transmural myocardial infarction in man using biologically active indium-111 (111In)-labeled autologous leukocytes was assessed in 36 patients. Indium-111 leukocytes (approximately 500 microCi) were injected i.v. 18-112 hours after the onset of chest pain. Cardiac imaging was performed 24 hours later with a mobile gamma camera. Twenty-one patients had positive images and 15 had negative images. The percent of positive images increased as the interval between infarction and 111In-leukocyte injection shortened; all patients injected within 24 hours of infarction had positive images. Patients with positive images were injected with 111In leukocytes earlier after infarction (mean +/- SEM, 43 +/- 4 vs 63 +/- 7 hours; p less than 0.05) and were younger (53 +/- 2 vs 65 +/- 3 years; p less than 0.05) than those with negative images. Several other parameters that could possibly have affected the imaging results were examined and were not significantly different in patients with positive and negative images. These included peak serum creatine kinase, location of infarction, incidence of pericarditis, use of antiinflammatory drugs (aspirin and indomethacin) or membrane-active antiarrhythmic drugs (lidocaine and procainamide), peripheral leukocyte count and cell labeling efficiency. The function of the labeled cell was similar in patients with positive and negative images. Six patients with acute infarction serving as controls and given free 111In oxine and six patients with stable coronary artery disease given 111In leukocytes all had negative cardiac images.

To assess the benefit of immediate surgical reperfusion over conventional medical treatment during the first acute evolving transmural myocardial infarction, 68 patients presenting within 4 hours of onset of chest pain were randomized into a medical group and a surgical group. Both groups were comparable for age, sex, coronary risk factors, location of infarct, and coronary anatomy. Radionuclide global ejection fraction at 48 hours after admission was 45 +/- 15% for the medical group versus 50 +/- 15% for the surgical group; at 3 months, ejection fraction values were 51 +/- 13% and 51 +/- 13%, respectively (p = NS). The average radionuclide wall-motion scores (normal, 3) at 3 months were 2 +/- 0.6 for the medical group and 2 +/- 0.7 for the surgical group. There were three (8.8%) early and four (11.7%) late deaths in the medical group and only one (2.9%) early death in the surgical group. Urgent surgical reperfusion in acute evolving myocardial infarction is a safe and effective procedure that appears to reduce early and late mortality but does not appear to improve left ventricular function.