Liver Cancer with Overlapping Myasthenia Gravis, Myocarditis, Seronegative Autoimmune Autonomic Ganglionopathy, and Myositis Symptoms Induced by Atezolizumab.

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

Primary Cardiac Angiosarcoma Accompanying Cardiac Tamponade.

A de novo cardiac malignant tumor is rare and sometimes challenging to diagnose. We encountered a 67-year-old man without any medical history complaining of dyspnea on effort. On admission, his hemodynamics were deteriorated due to cardiac tamponade, which was improved by percutaneous drainage of 1,200 mL pericardial effusion, showing 11.0 g/dL of hemoglobin. We suspected primary cardiac malignancy following multidisciplinary tests, and a cardiac biopsy via sternotomy demonstrated the definitive diagnosis of primary malignant tumor (angiosarcoma) infiltrating the right atrial myocardium. We initiated weekly paclitaxel therapy. Further studies are warranted to establish the optimal diagnostic and therapeutic strategy for de novo cardiac malignancy.

Sympathetic overactivation predicts body weight loss in patients with heart failure.

Neurohumoral activation is frequently observed in chronic heart failure (HF) patients who develop body weight (BW) loss. We therefore hypothesized that sympathetic overactivation can predict progression of BW loss in HF patients with reduced ejection fraction. We prospectively evaluated BW loss in 108 non-edematous HF in whom muscle sympathetic nerve activity (MSNA) was measured. Follow-up began on the day of first MSNA measurement. Patients with BW loss of ≥5% of baseline BW during the first year of follow-up were considered to be experiencing BW loss. Maximal BW loss (%) and time to first BW loss (i.e., ≥5%) were assessed. Primary cardiovascular endpoints included cardiovascular death and HF hospitalization. Predictors of outcomes were assessed on univariate, multivariate, and Kaplan-Meier analyses. BW loss ≥5% occurred in 14% of enrolled patients. Mean MSNA was significantly higher in the BW loss group than in the no-BW loss group (80 versus 58 bursts/100 beats; p < 0.001). Moreover, multivariate Cox proportional hazard regression analysis revealed MSNA as the only independent predictor of BW loss. Multiple linear regression analysis identified MSNA as the strongest independent marker of maximal BW loss, even after adjusting for univariate predictors. BW loss, MSNA and several variables also correlated significantly with poor outcomes in univariate analyses. However, multivariate analysis only showed MSNA and NYHA III/IV as independent prognostic predictors, while BW loss did not predict prognosis. MSNA offered the most sensitive marker of BW loss in HF patients, but MSNA, not BW loss, was an independent predictor of poor outcome.

Left ventricular pressure-volume relationship in conscious mice.

With the availability of transgenic models, the mouse has become an increasingly important subject for genetic-hemodynamic studies. Recently, we developed a technique to measure left ventricular (LV) pressure in conscious mice with an implanted LV polyethylene tube. We extended our new method by evaluating the LV pressure-volume relationship and examined the feasibility of this method in this study. We studied 17 male mice (age, 11-20 wk) with a conductance catheter inserted into the LV through the polyethylene tube. Load-independent parameters of contractility derived from pressure-volume relationship [slope of the end-systolic pressure-volume relationship (E(es)), slope of the maximum first derivative of LV pressure (dP/dt(max))-end-diastolic volume (EDV) relation, and preload-recruitable stroke work (PRSW)] were evaluated by inferior vena caval occlusion with an implanted snare. LV function assessed by this technique on two different days showed that the parameters were very similar, indicating reproducibility. Both linear and nonlinear regression analyses were performed for E(es). Contractility was enhanced by isoproterenol (E(es), 13.1 +/- 6.6 to 20.8 +/- 8.7 mmHg/microl; dP/dt(max)-EDV, 496 +/- 139 to 825 +/- 178 mmHg.s(-1).microl(-1); and PRSW, 110 +/- 23 to 127 +/- 21 mmHg), depressed by atenolol (E(es), 14.5 +/- 6.1 to 4.6 +/- 2.0 mmHg/microl; dP/dt(max)-EDV, 543 +/- 188 to 185 +/- 94 mmHg.s(-1).microl(-1); and PRSW, 117 +/- 20 to 70 +/- 15 mmHg) and isoflurane (E(es), 12.3 +/- 6.0 to 5.7 +/- 2.1 mmHg/microl; dP/dt(max)-EDV, 528 +/- 172 to 164 +/- 68 mmHg/s.microl; and PRSW, 124 +/- 19 to 48 +/- 10 mmHg), significantly. In conclusion, this is the first description of the LV pressure-volume relationship in conscious mice. These findings suggest that this method is feasible to detect changes of contractility in the conscious state, allowing serial assessment of pressure-volume-derived cardiac function indexes over time without anesthesia or repeated surgery.

VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.

Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1-3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.

Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts.

It has been shown that the adeno-associated virus (AAV) vector can deliver the VEGF gene efficiently into the ischemic mouse myocardium. However, the AAV genomes can be found in extracardiac organs after intramyocardial injection. To limit unwanted VEGF expression in organs other than the heart, we tested the use of the cardiac myosin light chain 2v (MLC-2v) promoter and the hypoxia-response element to mediate cardiac-specific and hypoxia-inducible VEGF expression. An AAV vector, MLCVEGF, with 250 bp of the MLC-2v promoter and nine copies of the hypoxia-response element driving VEGF expression, was constructed. Gene expression was studied in vitro by infection of rat cardiomyocytes, rat skeletal myocytes, and mouse fibroblasts with the vector and in vivo by direct injection of the vector into normal and ischemic mouse hearts. With MLCVEGF infection, VEGF expression was higher in cardiomyocytes than the other two cell lines and was hypoxiainducible. VEGF expression was also higher in ischemic hearts than in normal hearts. No VEGF expression was detectable in organs with detectable MLCVEGF vectors other than the heart. MLCVEGF-injected ischemic hearts had more capillaries and small vessels around the injection site, smaller infarct size, and better cardiac function than the negative controls. Hence, MLCVEGF can mediate cardiac-specific and hypoxia-inducible VEGF expression, neoangiogenesis, infarct-size reduction, and cardiac functional improvement.

New technique for measurement of left ventricular pressure in conscious mice.

Concern about the effects of anesthesia on physiological measurements led us to develop methodology to assess left ventricular (LV) pressure in conscious mice. Polyethylene-50 tubing filled with heparinized saline was implanted in the LV cavity through its apex via an abdominal approach and exteriorized to the back of the animal. This surgery was done under anesthesia with either an intraperitoneal injection of ketamine (80 mg/kg) and xylazine (5 mg/kg) (K+X) in 11 mice or isoflurane (ISF; 1.5 vol%) by inhalation in 14 mice. Postoperatively, mice were trained daily to lie quietly head first in a plastic cone. LV pressure, the first derivative of LV pressure (dP/dt), and heart rate (HR) in the conscious state were compared between the two groups at 3 days and 1 wk after recovery from surgery using a 1.4-Fr Millar catheter inserted into the LV through the tubing, with the mice lying quietly in the plastic cone. Acutely during anesthesia, K+X decreased HR (from 698 to 298 beats/min), LV systolic pressure (from 107 to 65 mmHg), and maximal dP/dt (dP/dt(max)) (from 15,724 to 4,445 mmHg/s), all P < 0.01. Similar but less marked negative chronotropic and inotropic effects were seen with ISF. HR and dP/dt(max) were decreased significantly in K+X mice 3 days after surgery compared with those anesthetized with ISF (655 vs. 711 beats/min, P < 0.05; 14,448 vs. 18,048 mmHg/s, P < 0.001) but increased to the same level as in ISF mice 1 wk after surgery. In ISF mice, recovery of function occurred rapidly and there were no differences in LV variables between 3 days and 1 wk. LV pressure and dP/dt can be measured in conscious mice with a micromanometer catheter inserted through tubing implanted permanently in the LV apex. Anesthesia with either K+X or, to a lesser extent, ISF, depressed LV function acutely. This depression of function persisted for 3 days after surgery with K+X (but not ISF) and did not recover completely until 1 wk postanesthesia.