Effects of low-dose aspirin on endothelial function in hypertensive patients.

BACKGROUND: It has been reported that administration of low-dose aspirin significantly reduces the frequency of major cardiovascular events in patients with hypertension and coronary artery disease. It is generally considered that the preventative effects of long-term aspirin administration on major cardiovascular events are due to the inhibition of platelet aggregation. HYPOTHESIS: It is not known whether administration of low-dose aspirin restores endothelium-dependent vasodilatation, and this study was undertaken to prove or disprove this question in patients with hypertension. METHODS: Flow-mediated endothelium-dependent dilatation and glyceryl trinitrate-induced endothelium-independent dilatation were investigated in 18 hypertensive patients and 10 normotensive control subjects. In the hypertensive patients, flow-mediated dilatation was investigated and cyclic guanosine monophosphate plasma (cGMP) was measured before and at 8 weeks after the administration of 162 mg of aspirin. RESULTS: Flow-mediated dilatation before aspirin administration was more reduced in the hypertensive patients than in the control subjects (6.4+/-2.0% vs. 11.3+/-2.3%, p <0.0001). Glyceryl trinitrate-induced dilatation before aspirin administration was similar in hypertensive patients and control subjects. Flow-mediated dilatation after aspirin administration was improved compared with that before aspirin administration (10.4+/-3.5% vs. 6.4+/-2.0%, p<0.0004). The cGMP product after aspirin administration was significantly higher than that before aspirin administration. CONCLUSIONS: Administration of low-dose aspirin may restore the endothelium-dependent vasodilatation in hypertensive patients. Furthermore, increased nitric oxide production may play a partial role in the improvement in endothelial function induced by administration of low-dose aspirin.

Giant negative T waves during interferon therapy in a patient with chronic hepatitis C.

Interferon-alpha (IFN-alpha) has been widely used for treatment of chronic hepatitis C in Japan. In general, cardiovascular adverse reactions are rare in association with IFN-alpha therapy. Here, a 64-year-old man with chronic active hepatitis C complained of fatigue, palpitation and depression, and developed atrial fibrillation with prominent negative T waves during IFN-alpha therapy. Echocardiogram showed septal and apical hypertrophy. Three days after discontinuation of IFN-alpha, subjective symptoms and atrial fibrillation subsided. It is unclear whether or not IFN-alpha induced the giant negative T waves with apical hypertrophy. We might observe the developing course of hepatitis C virus (HCV)-related myocardial hypertrophy by chance. Cardiovascular toxicity should be carefully monitored during IFN-alpha therapy even in patients with minor cardiac disease, such as premature ventricular contracture (PVC) and mild hypertension.

Nicorandil attenuates both temporal and spatial repolarization alternans.

T-wave alternans (TWA) on the electrocardiogram have been frequently associated with long QT syndrome (LQTS) and abrupt rate change. The present study investigated the effect of the potassium channel opener nicorandil on the repolarization alternans at the endocardium and the epicardium in the left ventricle. Electrocardiogram and transmural monophasic action potentials from the endocardium and the epicardium were simultaneously recorded in Langendorff-perfused guinea pig hearts. The hearts were paced at a basic cycle length (BCL) of 240 ms and the cycle length (CL) was abruptly shortened to 170 ms to induce repolarization alternans. Disopyramide and nicorandil were used to increase or attenuate repolarization alternans, respectively. Repolarization alternans were numerically expressed as the sum of the absolute difference between consecutive monophasic action potential durations at 90% repolarization (MAPD90) in the first 10 beats. In the control hearts, the MAPD90 alternans were 78.6 +/- 14.9 ms at the endocardium, and 49.8 +/- 58 ms at the epicardium (P = .03 endocardium vs epicardium). Disopyramide (2 microg/mL) increased the MAPD90 alternans to 186.6 +/- 30.6 ms at the endocardium and 116.4 +/- 16.5 ms at the epicardium, and enhanced the difference of repolarization alternans between the endocardium and the epicardium (transmural dispersion) from 28.8 +/- 11.3 ms to 70.2 +/- 18.7 ms (P = .02 vs controls). Nicorandil (400 ng/mL) suppressed the MAPD90 alternans to 79.6 +/- 16.3 ms at the endocardium and 56.0 +/- 11.8 ms at the epicardium, and attenuated the transmural dispersion to 23.6 +/- 6.0 ms (P = .02 vs disopyramide-administrated hearts). Our results suggest that nicorandil attenuates both temporal (beat-to-beat) and spatial (between the endocardium and the epicardium) repolarization alternans induced by the combination of cycle length changes and disopyramide administration.

Hepatitis C virus infection in a patient with dermatomyositis and left ventricular dysfunction.

Hepatitis C virus (HCV) infection is frequently associated with autoimmune disease. We present here a case of dermatomyositis manifested as heart failure in which HCV was detected from an endomyocardial biopsy sample. HCV infection may have contributed to the left ventricular dysfunction in this patient with dermatomyositis.

Involvement of Ca(2+) in antiarrhythmic effect of ischemic preconditioning in isolated rat heart.

We investigated the relationship between the effects of ischemic preconditioning (IPC) and Ca(2+) preconditioning (CPC) on reperfusion-induced arrhythmias. In the control group (noPC), Langendorff-perfused rat hearts were subjected to 5-min zero-flow global ischemia (I) followed by 15-min reperfusion (I/R). In ischemic preconditioning groups (IPC), the hearts were subjected to three cycles of 3-min global ischemia and 5-min reperfusion. In the CPC group, the hearts were exposed to three cycles of 3-min perfusion of higher Ca(2+) (2.3 mmol/l Ca(2+)) followed by 5-min perfusion of normal 1.3 mmol/l Ca(2+), and the hearts were then subjected to I/R. Verapamil was administered in several hearts of the IPC group (VR+IPC). Ventricular arrhythmias upon reperfusion were less frequently seen in the IPC and CPC groups than in the noPC and VR+IPC groups. IPC and CPC could attenuate conduction delay and enhance shortening of the monophasic action potential duration during ischemia. The ventricular fibrillation threshold measured at 1-min reperfusion was significantly higher in the IPC and CPC groups than in the noPC and VR+IPC groups. Verapamil completely abolished the salutary effects of IPC. These results demonstrate that Ca(2+) plays an important role in the antiarrhythmic effect of IPC during reperfusion.

Effects of cardiac sympathetic innervation on regional wall motion abnormality in patients with long QT syndrome.

AIM: To assess the spatial relation between regional cardiac sympathetic innervation and regional ventricular repolarisation indicated by ventricular wall motion abnormality in patients with congenital long QT syndrome. DESIGN: Regional percentage uptake and washout rate of (123)I metaiodobenzylguanidine (MIBG) were measured to assess cardiac sympathetic innervation in septum, anterior wall, lateral wall, and posterior wall. Left ventricular short axis images on echocardiography were digitised to reconstruct digitised M mode echocardiograms, from which left ventricular wall thickness curves were obtained. The wall thickening time (ThT) was defined as the period in which the instantaneous wall thickness exceeded 90% of the maximum wall thickness. The ThT was measured from the ventricular wall thickness curve at the same segments where regional percentage uptake and washout rate of (123)I MIBG were measured. PATIENTS: Seven patients with long QT syndrome. RESULTS: The regional washout rate (mean (SD)) of (123)I MIBG in patients with long QT syndrome was greater in the segments with decreased percentage uptake of (123)I MIBG than in those without (17.4 (10.6)% v 9.7 (16.5)%, p < 0. 03). ThT in segments both with and without decreased percentage uptake of (123)I MIBG was longer than in control subjects (p < 0. 0001). ThT was longer in the segments with decreased percentage uptake of (123)I MIBG than in those without (199 (70) ms v 150 (66) ms, p = 0.0018). CONCLUSIONS: Activation of regional cardiac sympathetic terminals is likely to participate in additional regional prolongation of ventricular repolarisation in patients with long QT syndrome.

High collagenolytic activity in spontaneously highly metastatic variants derived from a human pancreatic cancer cell line (SUIT-2) in nude mice.

Cell lines with high metastatic capacity to the lung were established by sequential passage of a human pancreatic cancer cell line (SUIT-2) through the lung of a nude mouse, via the lateral tail vein and from a subcutaneous inoculum. Cells of the parental SUIT-2 and sublines S2-VPx (x-cycle selection from SUIT-2 cells, by Vein-Pulmonary metastasis-culture) and S2-CPx (x-cycle selection, by Cutis-Pulmonary metastasis-culture) were injected intravenously or subcutaneously into nude mice to produce experimental or spontaneous lung metastasis. The S2-VP10 cell line produced pulmonary metastases in 100% of the nude mice, when injected intravenously. It failed, however, to produce more lung colonies than its parent cell line, when injected subcutaneously. The S2-CP8 cell line produced extensive pulmonary metastases in 100% of the nude mice, when injected either intravenously or subcutaneously. This study indicates that the nude mouse provided a good model for in vivo selection of metastatic cells from SUIT-2 cells both experimentally and spontaneously, and that the SUIT-2, S2-VPx, and S2-CPx cell lines will be valuable in the study of human cancer metastasis. We previously reported high levels of ezrin expression in the S2-VP10 and S2-CP8 cell lines. Here we show that these cell lines exhibit a greater capacity to invade or attach to various extracellular matrix components than the parent SUIT-2 cells. The S2-CP8 cell lines also exhibit greater level of type-I and type-IV collagen-degrading activity than the parent SUIT-2 cell line and the S2-VP10 cell line, which shows similar collagen-degrading activity to the parent SUIT-2 cells. In RT-PCR studies, SUIT-2, S2-CP8 and S2-VP10 cell lines constitutively expressed many matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP7, MMP-9, MMP-10 and MMP-14). These results suggest that some parameters that enhance adhesion and invasion are important to both experimental and spontaneous metastasis and the collagen degrading enzymes are predicted to play a key-role during spontaneous metastasis.

Attenuation of conduction delay by ischemic preconditioning reduces ischemia-induced ventricular arrhythmias.

Ischemic preconditioning has been acknowledged as a powerful method of decreasing ischemic injury. However, the antiarrhythmic mechanism of ischemic preconditioning during ischemia is unclear. We studied the effects of ischemic preconditioning on arrhythmias and cardiac electrophysiology during ischemia in Langendorff rat hearts (n = 44). In the non-preconditioned group (PC(-); n = 24), the hearts underwent 5-min zero-flow global ischemia without any prior ischemic preconditioning. In the preconditioned group (PC(+); n = 20), the hearts were preconditioned by three cycles of 3-min zero-flow global ischemia and 5-min reperfusion before undergoing 5-min global ischemia. Ischemic preconditioning reduced the incidence of ischemia-induced arrhythmias (PC(-); 38.9%, PC(+): 8.3%, p < 0.05), shortened monophasic action potential duration (MAPD, P < 0.05), attenuated conduction delay (conduction time; PC(-): 234.2%, PC(+): 173.4%, P < 0.05) and increased the ventricular fibrillation threshold. Although the shortening of MAPD in PC(-) hearts was not influenced by the presence or absence of arrhythmias, conduction time prolongation at 3-min was more obvious in PC(-) hearts with arrhythmia than in PC(-) hearts without arrhythmia (PC(-) with arrhythmia: 220.2%, PC(-) without arrhythmia: 190.7%, P < 0.05). We concluded that ischemic preconditioning could protect the rat hearts from ischemia-induced arrhythmias and postulated that attenuation of conduction delay during ischemia might be an important factor in the antiarrhythmic action of ischemic preconditioning.

Effects of ischemic preconditioning on reperfusion arrhythmias and electrophysiology in isolated rat hearts: it is not a role of KATP(+) channels.

OBJECTIVE: To investigate the effects of ischemic preconditioning (PC) and ATP sensitive K+ channels (KATP(+) opener nicorandil on reperfusion arrhythmias and electrophysiology. METHODS: Langendorff-perfused rat hearts were subjected to ischemic PC with three cycles of 2 minutes of global ischemia or infusion of KATP(+) opener nicorandil with subsequent 5 minutes global ischemia and reperfusion. The incidence of reperfusion arrhythmias, ventricular fibrillation threshold (VFT), effective refractory period (ERP) and monophasic action potential duration (MAPD) of the left and right ventricles were compared to those from control rat hearts. RESULTS: The results indicated that PC reduced the incidence of total arrhythmias and ventricular fibrillation during reperfusion (P < 0.05, vs controls). PC markedly delayed the onset of arrhythmia after reperfusion (P < 0.01, vs controls). PC significantly enhanced the VFT values during reperfusion and shortened the ERP and the MAPD during ischemia. VFT was restored more rapidly than that in controls. KATP+ opener nicorandil neither reduced the incidence of total arrhythmias and VF nor delayed arrhythmia onset. Nicorandil shortened ERP and MAPD90 without enhancing the VFT values, and VFT returned to normal as slowly as that in controls. CONCLUSIONS: We conclude that PC protects the globally ischemic rat hearts from reperfusion arrhythmias. The antiarrhythmic effect of PC is likely to be related to a significant increase of VFT. KATP(+) opener nicorandil has no potential antiarrhythmic action and KATP(+) channels may not play a major role in the antiarrhythmic effects of ischemic PC in isolated rat hearts.

Hormonal characteristics of primary aldosteronism due to unilateral adrenal hyperplasia.

A case of unilateral adrenocortical hyperplasia is presented. A 46-year-old woman with a 7-year history of hypertension and a 1-year-history of hypokalemia was diagnosed with primary aldosteronism. Computed tomography, magnetic resonance imaging, venous sampling and adosterol scintigraphy exhibited a functioning left adrenal mass. The plasma aldosterone concentration increased markedly when furosemide with upright posture and either captopril or adrenocorticotropin were administered. Plasma renin activity was suppressed below the detectable range. Aldosterone secretion displayed a circadian rhythm and was not suppressed by dexamethasone administration. The resected left adrenal mass was pathologically diagnosed as adrenocortical nodular hyperplasia. Unilateral adrenal hyperplasia involving the zona glomerulosa rarely has been reported, with varying and incompletely characterized hormonal characteristics. This case report and literature review suggest unilateral adrenal hyperplasia as a rare cause of hyperaldosteronism with characteristics intermediate between idiopathic hyperaldosteronism and aldosterone-producing adrenocortical adenoma, resembling the functional features of the adenoma more closely.

Relationship between electrocardiographic features and distribution of hypertrophy in patients with hypertrophic cardiomyopathy.

To evaluate the relationship between the distribution of hypertrophy and the electrocardiographic findings in patients with hypertrophic cardiomyopathy (HCM), 54 HCM patients were studied using magnetic resonance imaging. The patients were divided into 4 groups according to hypertrophic patterns: (i) hypertrophy only at the apex (group I, n=12); (ii) hypertrophy in both the apex and base (group II, n=20); (iii) hypertrophy only at the base with asymmetric septal hypertrophy (ASH) (group IIIa, n=17); and (iv) hypertrophy only at the base without ASH (group IIIb, n=5). Abnormal Q waves in leads II, III and aVF were found in 1/12, 3/20, 10/17 and 0/5, respectively, and in leads I and aVL they were found in 1/12, 8/20, 4/17 and 1/5, respectively. The largest negative T waves (mm) were found in group I (group I vs group II vs group IIIa vs group IIIb: 15.2+/-5.3, 8.2+/-6.1, 1.6+/-2.0, 0.8+/-1.3, respectively). The largest positive T waves (mm) were identified in group IIIb (3.8+/-3.0, 6.8+/-3.2, 5.8+/-3.6, 9.3+/-2.1, respectively). The presence of abnormal Q waves reflected regional hypertrophy in HCM patients but the configuration of T waves represented the difference in the localization of hypertrophy between the basal and apical segments.

Dispersion of regional wall motion abnormality in patients with long QT syndrome.

OBJECTIVE: To examine the left ventricular regional wall motion abnormality and to evaluate dispersion of this abnormality in patients with long QT syndrome. DESIGN: Left ventricular short axis images at basal and middle levels were recorded on videotape and digitised to reconstruct digitised M mode echocardiograms, from which left ventricular wall thickness curves were obtained. The wall thickening time (ThT) was defined as the period in which the instantaneous wall thickness exceeded 90% of the maximum wall thickness. ThT was measured at three segments in each of the septal and free wall sides of the left ventricle, a total of 12 segments. To examine the mechanical dispersion of the left ventricle, the difference between the maximum and minimum ThT of 12 segments in each subject was obtained. PATIENTS: Eight patients with congenital long QT syndrome (averaged QTc interval (SD) 509 (27) ms1/2) and 10 control subjects (QTc interval 397 (26) ms1/2) were examined. RESULTS: The averaged ThT values of the 12 segments pooled form all subjects were correlated with the QT intervals (r = 0.72, p < 0.005). Thus the averaged ThT in the long QT syndrome patients was longer than in the control subjects (p < 0.005). The segmental variation of ThT in the patients was greater than in the control subjects (p < 0.001). The dispersion of ThT in the patients was therefore larger than in control subjects (p < 0.005). However, the pattern of ThT variation in the patients varied according to the individual subject. CONCLUSIONS: There is not only electrical but also mechanical dispersion in the left ventricle of long QT syndrome patients. Regional assessment of ventricular wall motion may allow quantification of the spatial variation of wall motion abnormality.

P-selectin expression in a metastatic pancreatic tumor cell line (SUIT-2).

The human pancreatic tumor cell line SUIT-2 was derived from a metastatic lesion in the liver of a patient with pancreatic adenocarcinoma. SUIT-2 and clonal cell lines derived from it show spontaneous metastasis to lung and regional lymph nodes from s.c. nude mouse xenografts and were found to express P-selectin mRNA and protein. Surface expression of P-selectin protein was increased by exposure of the pancreatic tumor cells to thrombin, oxygen radicals, and trypsin, suggesting that common cellular mechanisms for regulating P-selectin surface expression exist among platelets, endothelial cells, and these pancreatic tumor cells. The finding that P-selectin is expressed by metastatic pancreatic tumor cells demonstrates that the range of cell types that express these adhesion molecules is broader than believed previously.

Effect of regional myocardial perfusion abnormalities on regional myocardial early diastolic function in patients with hypertrophic cardiomyopathy.

Nonuniform hypertrophy of the left ventricle is an important factor in regional diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). However, the effect of myocardial perfusion abnormalities on regional diastolic dysfunction has not been established in patients with HCM. We investigated the relationship between regional myocardial perfusion abnormalities and regional early diastolic function in 31 patients with HCM and 8 control patients. Short-axis images of the left ventricle recorded by cine magnetic resonance imaging were divided into ten blocks. The time-to-peak-wall-thickness-thinning rate (TPWR) and the wall thickness were measured in each block. Of the 310 blocks from the patients with HCM, 242 (78%) showed normal thallium-201 uptake (group 1), 40 (13%) showed slightly decreased uptake (group 2), and 28 (9%) showed markedly decreased uptake (group 3). There was no difference in the regional wall thickness among the three groups. The TPWR was longer in patients with HCM than in control patients. It was significantly longer in group 3 (190+/-45ms) than in group 1 (167+/-36 ms) and group 2 (160+/-31 ms). (P < 0.01). The linear regression slope of the relationship between the TPWR and the regional wall thickness was significantly steeper in group 3 than in groups 1 and 2 (P < 0.05). In conclusion, abnormalities in regional myocardial perfusion, in addition to regional hypertrophy, contributed to the regional early diastolic dysfunction in patients with HCM.

Myocardial clearance of I-123 metaiodobenzylguanidine in dilated cardiomyopathy.

We present the results of sequential imaging studies conducted in two patients with dilated cardiomyopathy whose responses to long-term beta-blocker therapy differed. We evaluated the time course of the myocardial clearance and the heart to upper mediastinal ratios of I-123 metaiodobenzylguanidine (MIBG) scintigraphy. In the first patient, the left ventricular ejection fraction as well as the clinical symptoms were improved by long-term beta-blocker therapy with a concurrent normalization of the myocardial clearance and the heart to upper mediastinal ratio of I-123 MIBG scintigraphy. The myocardial clearance and the upper mediastinal ratio of I-123 MIBG indicated no improvement in the second patient, and the left ventricular function did not change. The myocardial clearance and the heart to upper mediastinal ratio of I-123 MIBG scintigraphy were useful in evaluating the efficacy of long-term beta-blocker therapy in patients with dilated cardiomyopathy.

Assessment of regional early diastolic function using cine magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

In patients with hypertrophic cardiomyopathy (HCM), we conducted cine magnetic resonance imaging (MRI) studies in which our objectives were to quantify the regional early diastolic function of the left ventricle and to evaluate the relationship between regional diastolic function and hypertrophy. Short-axis images of the left ventricle were recorded by cine MRI in 8 control patients and 24 patients with HCM. The images were then divided into 10 blocks to evaluate regional early diastolic function. The regional wall-thickness-time curve, the radius-time curve, and their first-derivative curves were computed for each of the 10 blocks. There was no difference between the time-to-peak-radius-increasing ratio and the time-to-peak-wall-thickness-thinning ratio in the 10 blocks in the control patients. These 2 parameters in the patients with HCM were significantly longer than those in the control patients. There was also a significant linear correlation between the time-to-peak-wall-thickness-thinning ratio and regional wall thickness. Cine MRI was useful for evaluating regional early diastolic function, which is apparently related to regional hypertrophy, in patients with HCM.

Uniquely abnormal intracavitary flow during late systole and relaxation in hypertrophic obstructive cardiomyopathy with midventricular obstruction.

We describe a patient with hypertrophic cardiomyopathy who had a uniquely abnormal jet from the base to the apex during late systole and the relaxation period. This 48-year-old woman was admitted with exertional dyspnea and palpitations. Two-dimensional echocardiography revealed asymmetric septal hypertrophy and a left midventricular obstruction at the level of the papillary muscles. A high-velocity ejectional jet (peak velocity 4.8 m/s) directed toward the base during systole and an abnormal jet (peak velocity 2.2 m/s) directed toward the apex during late systole and the relaxation period were demonstrated through the midventricular obstruction site using Doppler echocardiography. The peak systolic pressure gradient between the apical and the basal chamber was 91 mmHg, and the peak systole pressure was higher in the apical chamber than in the basal chamber. However, a reverse pressure gradient was revealed between the two chambers during late systole and the relaxation period when the abnormal jet was demonstrated.

Evaluation of autonomic nervous activity in patients with congenital long QT syndrome by an analysis of RR variability.

Congenital long QT syndrome (LQTS) is a rare hereditary disease characterized by a prolonged QT interval and lethal ventricular tachycardia (Torsades de Pointes: TdP). The pathogenesis of LQTS and the induction of TdP have been thought to be closely related to autonomic nervous abnormalities. We examined autonomic activity in 13 LQTS patients by analyzing heart rate variability from 24 h Holter ambulatory electrocardiographic recordings without medications. In a frequency-analysis of RR variability, we calculated the power in the low-frequency domain (LF) and the high-frequency domain (HF) over 24 h. The ratio of LF to HF (an index of sympathetic nervous activity) was lower in LQTS patients than in controls, whereas HF (an index of parasympathetic nervous activity) was higher. Moreover, LQTS patients with TdP had lower abnormal sympathetic nervous activity than those without TdP. The index of autonomic nervous activity obtained using this method could be useful for evaluating the severity in LQTS.