Mitochondrial deformity confined to a single cardiomyocyte in human endomyocardial biopsy specimens: Report of 4 cases.

During electron microscopic examination of 156 consecutive human endomyocardial biopsy specimens, we found marked mitochondrial deformity within a single cardiomyocyte in each of 4 specimens. The deformed mitochondria were unevenly distributed, but the deformities were confined to the one cardiomyocyte. Those affected cardiomyocytes were accompanied by nonspecific degenerative changes such as nuclear hypertrophy and/or rarefaction of the myofibrils. Mitochondria in all other cells within the specimens appeared normal. Such an abnormality has never been reported to date. Each of the four cases was diagnosed with a different ailment: post-myocarditis, dilated cardiomyopathy, amyloidosis, and tachycardia-induced heart failure. However, all four cases were accompanied by left ventricular systolic dysfunction at biopsy. The very limited mitochondrial deformation may thus reflect a type of degenerative change that accompanies heart failure. .

Nonbacterial thrombotic endocarditis demonstrated by repeat echocardiography.

We report a case of nonbacterial thrombotic endocarditis (NBTE) in a patient with bladder cancer presenting with multiple cerebral infarctions. Initial transthoracic and transesophageal echocardiography did not show any abnormalities. However, repeat transthoracic and transesophageal echocardiography demonstrated a vegetation on the anterior leaflet of the mitral valve with mild mitral regurgitation and no evidence of leaflet destruction. Persistent high-grade fevers and leukocytosis were observed. The patient was suspected to have infective endocarditis. However, abdominal ultrasound and computed tomography scan revealed multiple metastatic masses, and serial blood cultures were negative. The patient was ultimately diagnosed with NBTE associated with multiple metastases of bladder cancer. This case suggests that even if echocardiography does not initially demonstrate any abnormalities in patients with embolism, it must be repeated at the recurrence of embolism, and that even if clinical signs of infection are documented, NBTE should be suspected in any cancer patient with thromboembolic events.

Three-dimensional reconstructive analysis of intracytoplasmic lumina found in ependymomas.

Three-dimensional reconstructive analyses revealed that the intracytoplasmic lumina found in ependymomas were actually formed by subsidence of an extracellular membrane, resembling a volcano. This finding was compatible with cytologic and electron microscopic findings. In addition, there were many tiny thorns resembling a holly leaf on the extracellular membrane, such that cilia and microvilli on the cellular membrane discontinued cell-to-cell tight junctions.

Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor.

OBJECTIVES: We sought to investigate the effect of dantrolene, a drug generally used to treat malignant hyperthermia, on the Ca2+ release and cardiomyocyte function in failing hearts. BACKGROUND: The N-terminal (N: 1-600) and central (C: 2000-2500) domains of the ryanodine receptor (RyR) harbor many mutations associated with malignant hyperthermia in skeletal muscle RyR (RyR1) and polymorphic ventricular tachycardia in cardiac RyR (RyR2). There is strong evidence that interdomain interaction between these regions plays an important role in the mechanism of channel regulation. METHODS: Sarcoplasmic reticulum vesicles and cardiomyocytes were isolated from the left ventricular muscles of dogs (normal or rapid ventricular pacing for 4 weeks), for Ca2+ leak, transient, and spark assays. To assess the zipped or unzipped state of the interacting domains, the RyR was labeled fluorescently with methylcoumarin acetate in a site-directed manner. We used a quartz-crystal microbalance technique to identify the dantrolene binding site within the RyR2. RESULTS: Dantrolene specifically bound to domain 601-620 in RyR2. In the sarcoplasmic reticulum isolated from pacing-induced failing dog hearts, the defective interdomain interaction (domain unzipping) had already occurred, causing spontaneous Ca2+ leak. Dantrolene suppressed both domain unzipping and the Ca2+ leak, demonstrating identical drug concentration-dependence (IC50 = 0.3 micromol/l). In failing cardiomyocytes, both diastolic Ca2+ sparks and delayed afterdepolarization were observed frequently, but 1 micromol/l dantrolene inhibited both events. CONCLUSIONS: Dantrolene corrects defective interdomain interactions within RyR2 in failing hearts, inhibits spontaneous Ca2+ leak, and in turn improves cardiomyocyte function in failing hearts. Thus, dantrolene may have a potential to treat heart failure, specifically targeting the RyR2.

AT1 receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+ -leak induced by oxidative stress.

BACKGROUND: The Ca(2+) regulatory proteins in the sarcoplasmic reticulum (SR) play a key role in the pathogenesis of heart failure. In the present study the effect of chronic beta-receptor-stimulation on cardiac and SR functions was assessed, with or without angiotensin-II receptor antagonist treatment recently reported to have anti-beta-adrenergic activity. METHODS AND RESULTS: Rats were treated with isoproterenol with (+) or without (-) candesartan (CAN) and then SR vesicles were isolated from the left ventricular muscle. Both Ca(2+)-uptake and the amount of SR Ca(2+)-ATPase were significantly lower in the CAN (-) group than in the shams, but those were almost normally restored in the CAN (+). Although the level of the protein kinase A (PKA)-phosphorylation of the SR Ca(2+) release channel, known as the ryanodine receptor (RyR2), was elevated in the CAN (-), no Ca(2+)-leak was detected. However, SIN-1 (O(2) (-) donor) induced Ca(2+)-leak in the CAN (-) at a 10-fold lower dose than in the sham and CAN (+). In cardiomyocytes, SIN-1 decreased cell shortening and the peak Ca(2+) transient and prolonged time from peak to 70% decline in CAN (-), again at 10-fold lower dose than in the sham and CAN (+). CONCLUSION: Chronic beta-receptor-stimulation did not induce any Ca(2+)-leak from the SR, whereas Ca(2+)-leak was easily induced when oxidative stress was applied to the PKA-phosphorylated RyR2. Candesartan not only improved Ca(2+)-uptake, but also prevented PKA-phosphorylation, rendering the SR less susceptible to Ca(2+)-leak.

Intima-media thickening of the radial artery after transradial intervention. An intravascular ultrasound study.

OBJECTIVES: We sought to assess the extent and nature of radial artery injury after transradial intervention (TRI) using intravascular ultrasound (IVUS). BACKGROUND: Although TRI has been developed to minimize bleeding and improve the quality of life, radial artery injury is a problem. METHODS: We studied 100 radial arteries in 100 consecutive patients who underwent coronary IVUS imaging. To assess the injury to the radial artery, we compared the radial artery findings between first-TRI patients (n = 48) and repeat-TRI patients (n = 52). Ten cross-sections at 5-mm intervals from the puncture site along a 50-mm distance were measured in each patient. RESULTS: In repeat-TRI patients, the lumen area (LA) and minimal lumen diameter (MLD) were smaller than those in first-TRI patients (p = 0.032 and p = 0.028, respectively), whereas the intima-media cross-sectional area (IMcsa) and intima-media thickness (IMT) were significantly greater than those in first-TRI patients (p < 0.01). In the proximal radial artery, there were no significant differences in the vessel area (VA), LA, IMcsa, or MLD between the two groups. In the distal radial artery, both LA and MLD were significantly smaller in repeat-TRI patients than in first-TRI patients (p < 0.01), whereas IMcsa and IMT were greater in repeat-TRI patients than in first-TRI patients (p < 0.01). However, VA did not differ between the two groups. CONCLUSION: The lumen diameters were smaller in repeat-TRI patients than in first-TRI patients due to intima-media thickening, especially in the distal radial artery. Care should be taken when the radial artery is used as a conduit in coronary artery bypass graft surgery, particularly in patients who have undergone TRI.

Angiomyoid proliferative lesion: an unusual stroma-rich variant of Castleman's disease of hyaline-vascular type.

The stroma-rich variant of Castleman's disease of hyaline-vascular type (CDHV) is a newly identified entity that shows overgrowth of a variety of stromal cells. Six CDHV patients showed proliferation of vasculature and actin-positive myoid cells in the expanded interfollicular (IF) area. There were three women and three men, and the median age was 29.5 years. Of the six lesions, four were located in the retroperitoneum, one in the neck, and one in the mediastinum. All patients were asymptomatic. Microscopically, the degree of widening of the IF area varied from slight overgrowth of the IF area (approximately 55% of the lymph node area) to vague nodularity and finally to the formation of prominent nodules. In the nodular lesions, lymph follicles were compressed and attenuated. In the IF area, there were numerous vessels and proliferation of spindle cells that possessed blunt nuclei. The long, slender, dendritic cytoplasms of the spindle cells were stained by alpha smooth muscle actin. The spindle cells were negative for desmin, CD34, factor VIII-related antigen, S-100, CD21, and CD68. No patient has had recurrence after simple excision. We maintain that these angiomyoid proliferative lesions in CDHV are of a hyperplastic nature. This condition encompasses proliferation of small vessels and myoid cells. Its characteristics include an asymptomatic, solitary nodule that predominantly develops in the retroperitoneum.