Small extra-adrenal pheochromocytoma causing severe hypertension in an elderly patient.

We report the case of a 67-year-old woman with severe hypertension caused by an extra-adrenal pheochromocytoma. The tumor was detected by 131I metaiodobenzylguanidine scintigraphy and it was found to be small (2 cm ø) by enhanced CT. After the extirpation of the tumor, the blood pressure of the patient immediately normalized. It should be taken into account that a small extra-adrenal pheochromocytoma can be one of the causes of secondary hypertension in elderly patients. Since small extra-adrenal pheochromocytomas are difficult to detect, it is also important to perform suitable examinations to establish the diagnosis. Furthermore, we emphasize the importance of an accurate diagnosis in elderly patients with pheochromocytoma, for they often have less symptomatology and more severe cardiovascular complications due to refractory hypertension than younger patients.

Acute myocardial infarction in a patient with essential thrombocythemia: successful treatment with percutaneous transluminal coronary recanalization.

A 65-year-old woman with essential thrombocythemia (ET) was admitted to hospital where she was diagnosed as acute myocardial infarction (AMI). Because of abundant thrombus of right coronary arteries, percutaneous transluminal coronary recanalization by administration of urokinase was selected as the reperfusion therapy, resulting in successful revascularization with Thrombolysis in Myocardial Infarction grade III coronary flow. The maximum creatine kinase reached 507 IU/L, and left ventriculography performed at 1 month after initiation of both anticoagulant and antiplatelet therapies revealed reduced motion in the inferior wall with an ejection fraction of 57%. Despite good recovery of left ventricular function, bleeding complications, such as epistaxis or ecchymoma, which did not require blood transfusion, occurred during the clinical course. Because ET causes not only thrombus formation but also bleeding tendency, it is very important to carefully follow-up any clotting abnormality in AMI patients with ET.

Effects of angiotensin II on the action potential durations of atrial myocytes in hypertensive rats.

Angiotensin II (Ang II) has been reported to indirectly influence atrial electrical activity and to play a critical role in atrial arrhythmias in hypertensive patients. However, it is unclear whether Ang II has direct effects on the electrophysiological activity of the atrium affected by hypertension. We examined the effects of Ang II on the action potentials of atrial myocytes enzymatically isolated from spontaneous hypertensive rats (SHRs). The action potentials were recorded by the perforated patch-clamp technique and the atrial expression of the receptors AT1a and AT2 was measured by radioimmunoassay. Ang II significantly shortened the action potential durations (APDs) of SHRs without changes in the resting membrane potentials (RMPs). Pretreatment with selective AT1a blockers abolished the Ang II-induced reduction of atrial APDs of SHRs; however, a selective AT2 blocker did not, which was consistent with the results of the receptor assay. Pretreatment with phosphatidylinositol 3 (PI3)-kinase inhibitor, phospholipase C inhibitor, or protein kinase C (PKC) inhibitor abolished the Ang II-induced shortening of atrial APDs, but pertussis toxin and protein kinase A (PKA) inhibitor did not. To study the effects of chronic AT1a inhibition on Ang II-induced shortening of atrial APD, SHRs were treated with AT1a blocker for 4 weeks. AT1a blocker abolished the Ang II-induced reduction of atrial APDs of SHRs and also significantly lowered their blood pressure. In conclusion, Ang II shortened atrial APDs of SHRs via AT1a coupled with the Gq-mediated inositol triphosphate (IP3)-PKC pathway. Our findings indicated that Ang II caused atrial arrhythmias in hypertensive patients by shortening the effective refractory period of the atrium.

Transient left ventricular apical ballooning in a patient with bicuspid aortic valve created a left ventricular thrombus leading to acute renal infarction.

A 44-year-old woman had tako-tsubo-like ventricular dysfunction with chest pain and ST segment elevation on the ECG. Echocardiography revealed a bicuspid aortic valve with moderate to severe aortic regurgitation. She developed mild heart failure during the clinical course, but the medication (furosemide, enalapril, and asprin) had to be stopped because of skin eruptions. Four weeks after ceasing the antiplatelet agent, she was re-admitted with acute renal infarction. Enhanced chest computed tomography revealed a filling defect in the left ventricle and echocardiography showed a high echogenic mass in the left ventricular apical wall. These findings strongly suggested that the renal infarction was caused by an embolism derived from a left ventricular thrombus that formed during the clinical course of the transient left ventricular apical ballooning. Anticoagulation therapy with urokinase and warfarin successfully lysed the thrombus. Left ventricular thrombus should be considered a complication of transient left ventricular apical ballooning, especially in patients with organic heart disease.

Atrial natriuretic peptide inhibits cardiomyocyte hypertrophy through mitogen-activated protein kinase phosphatase-1.

Cardiac hypertrophy is formed in response to hemodynamic overload. Although a variety of factors such as catecholamines, angiotensin II (AngII), and endothelin-1 (ET-1) have been reported to induce cardiac hypertrophy, little is known regarding the factors that inhibit the development of cardiac hypertrophy. Production of atrial natriuretic peptide (ANP) is increased in the hypertrophied heart and ANP has recently been reported to inhibit the growth of various cell types. We therefore examined whether ANP inhibits the development of cardiac hypertrophy. Pretreatment of cultured cardiomyocytes with ANP inhibited the AngII- or ET-1-induced increase in the cell size and the protein synthesis. ANP also inhibited the AngII- or ET-1-induced hypertrophic responses such as activation of mitogen-activated protein kinase (MAPK) and induction of immediate early response genes and fetal type genes. To determine how ANP inhibits cardiomyocyte hypertrophy, we examined the mechanism of ANP-induced suppression of the MAPK activation. ANP strongly induced expression of MAPK phosphatase-1 (MKP-1) and overexpression of MKP-1 inhibited AngII- or ET-1-induced hypertrophic responses. These growth-inhibitory actions of ANP were mimicked by a cyclic GMP analog 8-bromo-cyclic GMP. Taken together, ANP directly inhibits the growth factor-induced cardiomyocyte hypertrophy at least partly via induction of MKP-1. Our present study suggests that the formation of cardiac hypertrophy is regulated not only by positive but by negative factors in response to hemodynamic load.

Protective effect of edaravone against hypoxia-reoxygenation injury in rabbit cardiomyocytes.

1 We examined whether edaravone (Eda), a clinically available radical scavenger, directly protects cardiomyocytes from ischemia/reperfusion (I/R) injury, and whether the timing of its application is critical for protection. 2 Cardioprotective effects of edaravone were tested in the modified cell-pelleting model of ischemia and under exogenous oxidative stress (hydrogen peroxide: H2O2) in isolated adult rabbit ventricular cells. Cell death and reactive oxygen species (ROS) generation were detected using propidium iodide (PI) and DCFH-DA, respectively. These parameters were evaluated objectively using flow cytometory. 3 Hypoxia and reoxygenation aggravated the proportion of dead cells from 32.2+/-1.8% (Baseline) to 51.3+/-2.7% (Control). When 15 microm edaravone was applied either throughout the entire experiment (Through) or only at reoxygenation (Reox), cell death was significantly reduced to 39.9+/-1.8% (P<0.01 vs Control) and 43.3+/-2.5% (P<0.05 vs Control), respectively. In contrast, when edaravone was applied 10 min after reoxygenation, its protective effect disappeared. Cardioprotection by edaravone was more remarkable than that afforded by other free radical scavengers, such as ascorbate and superoxide dismutase (SOD). There is a positive correlation between the cardioprotective effect of edaravone and the extent of ROS reduction. 4 Edaravone blunted the H2O2-induced changes in electrical properties, and significantly prolonged the time to contracture induced by H2O2 in single ventricular myocytes. 5 Taken together, edaravone directly protects cardiomyocytes from I/R injury by attenuating ROS production, even when applied at the time of reoxygenation, suggesting that edaravone could be a potent cardioprotective therapeutic agent against hypoxia-reoxygenation injury.

Acute secondary gastrointestinal amyloidosis in a patient with rheumatoid arthritis.

Secondary amyloidosis is well recognized as a severe complication in the late stages of rheumatoid arthritis (RA). However, there have been few reported cases of secondary amyloidosis developing early during the course of RA. We here report the case of a 35-year-old woman, in whom RA who had been diagnosed 1 year before, with intractable watery diarrhea as a symptom of RA-induced secondary intestinal amyloidosis. Combination treatment with intravenous hyperalimentation, corticosteroids, and methotrexate (MTX) resulted in a dramatic improvement of her symptoms and objective findings of serological abnormalities. Subsequent administration of corticosteroids and MTX resulted in long-term survival without recurrence. This case indicates that we should be alert for the development of secondary amyloidosis, even in patients with a short history of RA, when the disease is active. Furthermore, combination therapy with intravenous hyperalimentation and strong immunosuppressive agents seems to be very efficacious in the treatment of RA-associated secondary intestinal amyloidosis.

Coordinate induction of AMP deaminase in human atrium with mitochondrial DNA deletion.

Despite the heteroplasmic lower population of mitochondrial (mt) DNA deletion, mtDNA deletion is significantly related to the loss of atrial adenine nucleotides. To elucidate its mechanism, we examined the frequency of a 7.4-kb mtDNA deletion, the concentration of adenine nucleotides, and the activity of AMP catabolic enzymes in 10 human right atria obtained from cardiac surgery, using quantitative PCR, HPLC, and immunoprecipitations. The atrial concentrations of ATP, ADP, AMP, and the total adenine nucleotides were significantly lower in patients with deletion than those in patients without deletion, despite the lower frequency of their deletion. The activities of total AMP deaminase (AMPD), liver-type (AMPD 2), and heart-type isoform (AMPD 3) were significantly higher in patients with deletion than in patients without deletion, although there was no significant difference in the cytosolic 5(')-nucleotidase among them. In conclusion, mtDNA deletion coordinately induces AMP deaminase to contribute to the loss of atrial adenine nucleotides through degrading AMP excessively.

Parathyroid hormone-related protein is produced in the myocardium and increased in patients with congestive heart failure.

PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.

Effects of the angiotensin-converting enzyme inhibitor alacepril on exercise capacity and neurohormonal factors in patients with mild-to-moderate heart failure.

1. Alacepril is a long-acting, sulphydryl-containing angiotensin-converting enzyme inhibitor. Data are limited regarding the effects of alacepril on exercise tolerance in patients with chronic heart failure (CHF). The aim of the present study was to determine the effects of chronic alacepril treatment on exercise capacity and neurohormones in patients with CHF. 2. The effects of 12 weeks treatment with alacepril on clinical, echocardiographic and cardiopulmonary exercise variables were studied in 18 CHF patients (mean age: 63 +/- 2 years; New York Heart Association (NYHA) class I n = 6, class II n = 10, class III n = 2) in a cross-over fashion. Resting levels of plasma noradrenaline, renin-angiotensin system activity and natriuretic peptides were evaluated. 3. Treatment with alacepril significantly improved NYHA functional class and decreased cardiothoracic ratio (60.1 +/- 2.0 vs 58.1 +/- 1.9% for baseline vs alacepril, respectively; P < 0.01). Cardiac dimensions by echocardiogram were decreased after alacepril therapy. Peak Vo2 (17.7 +/- 1.2 vs 19.5 +/- 1.3 mL/min per kg; P < 0.01) and anaerobic threshold (11.7 +/- 0.6 vs 13.2 +/- 0.9 mL/min per kg; P < 0.01) increased with alacepril treatment. Plasma noradrenaline and plasma angiotensin II levels were not altered, but plasma aldosterone (77.7 +/- 13.5 vs 51.7 +/- 9.7 pg/mL; P < 0.01), atrial natriuretic peptide (ANP; 86.5 +/- 20.3 vs 43.6 +/- 7.6 pg/mL; P < 0.05) and brain natriuretic peptide (BNP; 222.7 +/- 59.3 vs 117.7 +/- 34.3 pg/mL; P < 0.05) levels decreased after alacepril treatment. 4. These results suggest that treatment with alacepril improves functional status and exercise capacity in patients with mild-to-moderate CHF. Neurohormones were favourably influenced by alacepril therapy, with significant decreases in plasma aldosterone, ANP and BNP levels.

Troglitazone improves cardiac function in patients with congestive heart failure.

Troglitazone increased cardiac output and stroke volume, as a result of decreased peripheral resistance, in diabetic patients with normal cardiac function. The cardiovascular effects of troglitazone in patients with heart failure are unknown. The aim of the study was to evaluate the cardiovascular effects of troglitazone in patients with heart failure. Blood pressure and echocardiographic findings were evaluated before and 1, 2, 3 and 4 hours after a single dose of troglitazone (400 mg) or placebo, in eight type II diabetic patients with congestive heart failure. The plasma catecholamines and coefficient of variance of RR intervals (CVRR) were also measured. Neither heart rate nor blood pressure changed after the administration of troglitazone. Left ventricular (LV) end-diastolic dimension did not change either, however, the LV end-systolic dimension significantly decreased compared with its baseline value and with that of the placebo group. On the other hand, the % fractional shortening and the E/A ratio increased significantly after troglitazone. The LV end-diastolic volume did not change, whereas the LV end-systolic volume significantly decreased. The stroke volume and the LV ejection fraction significantly increased compared with its baseline value and with that of the placebo group. The peripheral vascular resistance did not change after the administration of troglitazone, whereas plasma catecholamines significantly decreased, and CVRR remained unchanged in both groups. These hemodynamic changes suggest that a single oral dose of troglitazone induced inotropy without activation of the sympathetic nervous system.

Isolated autonomic cardiovascular neuropathy in a patient with primary Sjögren syndrome: a case of successful treatment with glucocorticoid.

Autonomic failure is rare in patients with Sjögren syndrome (SS). We report the case of a 46-year-old woman with severe autonomic cardiovascular failure, manifested by incapacitating postural hypotension, as the first symptom of primary SS. Treatment with glucocorticoid resulted in a dramatic improvement of her symptoms and objective findings of autonomic cardiovascular dysfunction. We suggest that SS should be considered in patients with idiopathic autonomic cardiovascular neuropathy, especially in those with idiopathic orthostatic hypotension. Furthermore, glucocorticoid therapy seems to be very efficacious in the treatment of SS-associated autonomic cardiovascular neuropathy.

Sodium calcium exchanger plays a key role in alteration of cardiac function in response to pressure overload.

The Na+-Ca2+ exchanger (NCX) on the plasma membrane is thought to be the main calcium extrusion system from the cytosol to the extracellular space in many mammalian excitable cells, including cardiac myocytes. However, the pathophysiological role of NCX in the heart is still unclear because of the lack of known specific inhibitors of NCX. To determine the role of NCX in cardiac contraction and the development of cardiac hypertrophy, we imposed pressure overload on the heart of heterozygous NCX knockout (KO) mice by constricting transverse aorta, and examined cardiac function and morphology 3 wk after operation. Although there was no difference in cardiac function between sham-operated KO mice and sham-operated wild-type (WT) mice, KO mice showed higher left ventricular pressure and better systolic function than WT mice in response to pressure overload. Northern blot analysis revealed that mRNA levels of sarcoplasmic reticulum Ca2+-ATPase were reduced by pressure overload in left ventricles of WT but not of KO mice. However, hypertrophic changes with interstitial fibrosis were more prominent in KO mice than WT mice. These results suggest that reduction of NCX results in supernormalized cardiac function and causes marked cardiac hypertrophy in response to pressure overload.