Endocardial Invasion of Lung Cancer Undiagnosable before Autopsy.

A 59-year-old male patient presented with left chest discomfort on admission. His medical history included encephalitis in childhood and his smoking history was 20 cigarettes per day for 40 years. A physical examination showed an anemic and edematous face with weak respiratory sounds in the left lung. The patient had elevated calcium levels and decreased hemoglobin and potassium. His parathyroid hormone-related protein level was elevated. Thoracic radiography showed cardiomegaly and computed tomography revealed a left lung mass with invasion of the heart and pleural effusion. Magnetic resonance imaging showed endocardial invasion of the tumor mass. Gallium-68 imaging revealed positive accumulation in the region surrounding the heart. No diagnoses were possible upon frequent cytology of his sputum and pleural effusion. The patient died from congestive heart failure with anoxia 38 days after admission. An autopsy revealed tumoral mass occlusion in the left main bronchus and tumoral invasion of the left atrium, left ventricle, and aorta.

Spontaneous remission of epstein-barr virus-positive diffuse large B-cell lymphoma of the elderly.

A 94-year-old female patient presented with anorexia and left axillar lymphadenopathy on admission. Her past history was angina pectoris at 83 years of age and total gastrectomy due to gastric cancer at 87 years. The family history revealed that her son had had a malignant lymphoma, the histopathological diagnosis of which was diffuse large B-cell lymphoma. A physical examination showed both cervical, axillar, and inguinal lymphadenopathy without tenderness. She had elevated lactate dehydrogenase, ferritin, and soluble interleukin-2 receptor (sIL-2R). Whole-body computed tomography confirmed the cervical, axillary, and inguinal lymphadenopathy. Gallium-68 imaging revealed positive accumulation in these superficial lymph nodes. A right inguinal lymph node biopsy showed features of Epstein-Barr virus-associated lymphoproliferative disorder. Immunohistological studies on this lymph node biopsy showed CD20-positive large cells, CD3-positive small cells, and CD30-partly-positive large cells. In situ hybridization showed Epstein-Barr virus-positive, LMP-partly-positive, and EBNA2-negative cells. She refused chemotherapy as her son had died from hematemesis during chemotherapy. She received intravenous hyperalimentation for 1 month after admission. No palpable lymph nodes were identified by physical examination or computed tomography 3 months after admission, and regression of lactate dehydrogenase, ferritin, and sIL-2R was observed. She recovered from anorexia and was discharged. She died from pneumonia 10 months later after initial symptoms of anorexia. The autopsy showed no superficial lymphadenopathy.

Upregulation of cardiac ghrelin mRNA in leptin-deficient and leptin receptor-deficient mice with viral myocarditis.

Expression of cardiac and gastric ghrelin messenger (m) RNA, together with heart and body weights, were measured in leptin-deficient (ob) and leptin receptor-deficient (db) mice with heart failure induced by viral myocarditis. Significant elevations in cardiac ghrelin mRNA levels and heart weight were observed in ob and db mice 10 days after viral inoculation compared with baseline values. Expression of gastric ghrelin mRNA was not upregulated in ob and db mice on day 10. The elevated expression of cardiac ghrelin mRNA seems to compensate for the lack of upregulation in gastric ghrelin mRNA.

[Changes in serum malondialdehyde-modified low-density lipoprotein in patients with acute myocardial infarction and stable angina pectoris treated by coronary angioplasty].

OBJECTIVES: Serum malondialdehyde-modified low-density lipoprotein(MDA-LDL) was measured as a marker of oxidative stress, and the changes in serum MDA-LDL compared in patients with acute myocardial infarction and stable angina pectoris treated by percutaneous transluminal coronary angioplasty (PTCA). METHODS: Forty-one patients with acute myocardial infarction or stable angina pectoris were admitted to our hospitals between January 2000 and June 2000. Direct PTCA was performed in 17 patients(MI group) and elective PTCA in 24 patients(AP group). Coronary angiography was performed in nine control subjects(control group). Serum MDA-LDL was measured in the peripheral venous blood before and immediately after procedures in each group(normal range 20-80 U/l). RESULTS: There were no significant differences in patient characteristics, except age, between the MI group and AP group. Serum MDA-LDL was elevated above the normal range before the procedure in both groups(MI group 104.7 +/- 52.0 U/l, AP group 99.7 +/- 42.8 U/l), and significantly decreased immediately after the procedure(MI group 61.3 +/- 25.6 U/l, AP group 62.0 +/- 29.6 U/l), but there were no significant differences between the two groups. Serum MDA-LDL was elevated before the procedure (99.3 +/- 48.9 U/l) in the control group and significantly decreased immediately after the procedure(61.7 +/- 26.2 U/l). However, these values did not differ from the values before and immediately after the procedure in the MI group and the AP group. The percentage changes in serum MDA-LDL before and immediately after the procedure were -38 +/- 16% in the MI group, -37 +/- 17% in the AP group and -36 +/- 20% in the control group, and there were no significant differences between the three groups. CONCLUSIONS: No significant difference in the changes in serum MDA-LDL was observed between patients with acute myocardial infarction and stable angina pectoris treated by PTCA. However, anticoagulants may affect the MDA-LDL measurements directly, because similar changes in serum MDA-LDL were observed in control subjects after only coronary angiography.

Increased cardiac weight in interleukin-6 transgenic mice with viral infection accompanies impaired expression of natriuretic peptide genes.

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) regulate cardiac hypertrophy. We investigated ventricular alterations of ANP and BNP in interleukin-6 (IL-6) transgenic mice (TG) and wild type (WT) mice with or without viral infection. The ANP and BNP mRNA/GAPDH mRNA ratios in the ventricles of IL-6 TG mice were twice that of WT mice, but were not increased significantly by viral inoculation. In WT mice, both ANP and BNP responses were significantly increased in the ventricles of mice 10 days after encephalomyocarditis (EMC) viral inoculation. Cardiac weight in IL-6 TG mice was significantly greater than in WT 10 days after viral inoculation. Left ventricular wall thickness and the diameter of ventricular myocytes also were greater in IL-6 TG than WT after viral infection. Primary cultures of neonatal rat cardiac myocyte showed that IL-6 increased ANP and BNP mRNA expression in a dose-responsive fashion. In summary, overexpression of ANP and BNP occurs in the ventricles of IL-6 TG mice, along with increased cardiac weight after infection with EMC virus, and impaired responses in the expression of ANP and BNP.

Beneficial effect of muscarinic-2 antagonist on dilated cardiomyopathy induced by autoimmune mechanism against muscarinic-2 receptor.

We have previously shown that a peptide corresponding to the sequence of the second extracellular loop of the human muscarinic-2 (M2) receptor (M2-peptide) was able to induce an autoimmune cardiomyopathy in rabbits. In this study, we investigated the effect of M2-antagonist (otenzepad) on M2-peptide-induced cardiomyopathy in rabbits. New Zealand White rabbits were divided into four groups: 1) control group, saline injection; 2) M2-peptide group, M2-peptide injection; 3) M2-antagonist group, otenzepad (30 mg/day) orally and saline injection; and (4) M2-antagonist + M2-peptide group, otenzepad (30 mg/day) orally and M2-peptide injection. The study duration was 1 year. Saline or peptide was injected once a month. All rabbits in both the M2-peptide group and the M2-antagonist + M2-peptide group had high titers of anti-M2-autoantibodies in their sera. Rabbits in the M2-peptide group showed an increase in heart weight, wall thinning and dilatation of the right ventricle. On the contrary, rabbits in the M2-antagonist + M2-peptide group had normal heart weight and shape. All rabbits in the M2-peptide group showed multifocal degeneration and necrosis of myocardial cells with moderate infiltration of inflammatory cells, while four rabbits in the M2-antagonist + M2-peptide group showed slight infiltration of inflammatory cells with normal myocardial cells and interstitium, and another three showed no histological changes in the hearts. In conclusion, M2-antagonist protects the myocardium from injury induced by autoimmune mechanism against M2-muscarinic receptor.

The potent role of increased sympathetic tone in pathogenesis of essential hypertension with neurovascular compression.

OBJECTIVE: To study the role of increased sympathetic tone in pathogenesis of hypertension in patients with essential hypertension with neurovascular compression. METHODS: Twenty-three patients with essential hypertension, 13 patients with secondary hypertension, and 46 normotensive subjects were investigated. Neurovascular compression was evaluated by MRT. The power spectral components of heart rate variability as indices of autonomic nerve tone were determined to investigate the possibility that sympathetic tone mediates the neurovascular compression-induced increase in blood pressure. RESULTS: Neurovascular compression of the rostral ventrolateral medulla (RVLM) was observed in 70% of essential hypertension group, none of secondary hyperension group and 16% of normotensive group (P < 0.001). The age-adjusted low-frequency power spectral density (A-PSD) (0.04 to 0.15 Hz), which is an index of sympathetic tone, was significantly higher in patients with essential hypertension (139.5 +/- 6.7%) with neurovascular compression than in essential hypertension patients without neurovascular compression (92.2 +/- 6.8%), normotensive subjects with (102.8 +/- 13.0%) and without neurovascular compression (100.1 +/- 4.1%), and patients with secondary hypertension (95.7 +/- 10.2%) (P < 0.001). There was no significant difference in the high-frequency A-PSD (0.15 to 0.40 Hz), which is an index of vagal tone, among groups. CONCLUSIONS: Neurovascular compression was not always associated with an increase in sympathetic nerve tone. Hypertension was present in subjects with neurovascular compression, who had increased sympathetic tone but not in those with normal sympathetic tone. An increase in sympathetic tone may mediate the neurovascular compression-induced increase in blood pressure. Journal of Human Hypertension (2000) 14, 807-811

Noninvasive, continuous evaluation of peripheral vascular resistance in humans.

We sought a noninvasive alternative method of monitoring peripheral vascular resistance continuously in humans, based on the analysis of arterial pressure waveforms. Radial arterial pressure waveforms were recorded noninvasively with a tonometer and analysed using a neural network method. To test the accuracy of this method, the peripheral vascular resistance was also determined by an invasive thermodilution method using a Swan-Ganz catheter in 20 subjects. To test the method in a clinical application, peripheral vascular resistance was determined by the noninvasive method before and after administration of nifedipine in 6 patients with essential hypertension. Neural network analysis of waveforms reliably yielded values between 0.00 and 1.00. Peripheral vascular resistance determined by neural network analysis and according to the invasive method showed a significant (p< 0.005) positive linear correlation. The peripheral vascular resistance measured by neural network analysis showed a significant (p< 0.05) decrease 30 min after administration of nifedipine, paralleling a decrease in blood pressure. Neural network analysis of tonometric radial artery waveforms provides an accurate, noninvasive, and continuous index of peripheral vascular resistance in human subjects. This simple method should permit more extensive homodynamic studies and larger epidemiological surveys in contrast to those undertaken using invasive techniques.

Beneficial effect of angiotensin-converting enzyme inhibitor on dilated cardiomyopathy induced by autoimmune mechanism against beta1-adrenoceptor.

We have shown that a peptide corresponding to the sequence of the second extracellular loop of the human beta1-adrenoceptor (beta1-peptide) was able to induce an autoimmune cardiomyopathy in rabbits. In this study, we examined the effect of angiotensin-converting enzyme inhibitor (ACEI) on beta1-peptide-induced cardiomyopathy. Rabbits were divided into four groups: (1) control group (n= 6) receiving saline injection; (2) beta1-peptide group (n = 8) immunized with beta1-peptide; (3) ACEI group (n = 6), lisinopril (3 mg/day) given orally and receiving saline injection; and (4) ACEI + beta1-peptide group (n = 7), lisinopril (3 mg/day) given orally and immunized with beta1-peptide. Our results showed that, after 1 year, all rabbits in the beta1-peptide group had an increase in heart weight, wall thinning and dilatations of both ventricles as compared with rabbits in the ACEI + beta1-peptide group that had normal heart weight and shape. All rabbits in the beta1-peptide group exhibited multifocal degeneration and necrosis of myocardial cells with moderate infiltration of inflammatory cells. In the ACEI + beta1-peptide group, three rabbits showed focal degeneration and necrosis of myocardial cells accompanied by mononuclear cells. The lesions in this group were apparently less marked than those in the beta1-peptide group. In conclusion, ACEI protects the myocardium from injury induced by an autoimmune mechanism against beta1-adrenoceptor.

Active immunization of combined beta1-adrenoceptor and M2-muscarinic receptor peptides induces cardiac hypertrophy in rabbits.

BACKGROUND: The high prevalence of patients with dilated cardiomyopathy (DCM) with anti-beta1-adrenoceptor and/or anti-M2-muscarinic receptor autoantibodies in their sera has been observed. However, the pathophysiological role of these autoantibodies in the development of cardiomyopathy is unknown. We previously reported an experimental model of early-stage DCM-like cardiomyopathy induced by immunizing rabbits for 1 year with synthetic peptides corresponding to the sequence of the second extracellular loop of either beta1-adrenoceptor or M2-muscarinic receptor. Because approximately half the sera of patients with DCM that recognize one of the two receptor sequences also recognize the second sequence, a model was created in rabbits simultaneously immunized with the synthetic peptides corresponding to the second extracellular loop of the beta1-adrenoceptor and M2-muscarinic receptor. METHODS AND RESULTS: All rabbits (n = 8) immunized with both peptides had a high titer of both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies in their sera, whereas none of the sera from control rabbits injected with saline (n = 9) was positive. No significant cross-reaction with peptides other than those used for immunization was found. The weight of the hearts of immunized rabbits increased significantly. The hearts of immunized rabbits showed marked concentric left ventricular hypertrophy with mild inflammatory cell infiltration. In these rabbits, mild or moderate interstitial fibrosis was also observed. In electron micrographs, immunized rabbits showed focal myofibrillar lysis, loss of myofilament, and a marked increase in the number of mitochondria and deposition of dense granules in both sarcoplasm and myofibrils. Conversely, one of the control rabbits showed scant mononuclear cell infiltration. However, in this control rabbit, no significant alteration was found by electron microscopy. CONCLUSION: Our results showed the coexistence of both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies in the sera has pathophysiological importance, shown by their ability to induce cardiac hypertrophy in rabbits.

Residual cardiomyocytes and scintigraphic findings in advanced coronary artery disease: correlation with technetium-99m-tetrofosmin and thallium-201 single photon emission computed tomography.

A 68-year-old man suffering from chronic heart failure due to coronary artery disease (CAD) underwent rest technetium-99m (99mTc)-tetrofosmin and thallium-201 (201Tl) with reinjection studies, but died thereafter. The heart was removed and sectioned into short-axis slices and examined by gross and microscopic pathologic methods. A close correlation between the amount of residual cardiomyocytes and the level of regional tracer activity in the left ventricular wall was obtained for redistribution 201Tl, reinjection 201Tl and rest 99mTc tetrofosmin images. The correlation coefficients were r=0.901 for the 201Tl redistribution images, r=0.913 for the 201Tl reinjection images and r=0.917 for the rest 99mTc-tetrofosmin images. This case report provides further evidence of the validity of SPECT tetrofosmin imaging for the determination of myocardial viability in CAD.

Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice.

Many lines of evidence have suggested that angiotensin II (AngII) plays an important role in the development of cardiac hypertrophy through AngII type 1 receptor (AT1). To determine whether AngII is indispensable for the development of mechanical stress-induced cardiac hypertrophy, we examined the activity of mitogen-activated protein kinase (MAPK) family and the expression of the c-fos gene as hypertrophic responses after stretching cultured cardiac myocytes of AT1a knockout (KO) mice. When cardiac myocytes were stretched by 20% for 10 min, extracellular signal-regulated protein kinases (ERKs) were strongly activated in KO cardiomyocytes as well as wild type (WT) myocytes. Both basal and stimulated levels of ERKs were higher in cardiomyocytes of KO mice than in those of WT mice. Activation of another member of the MAPK family, p38(MAPK), and expression of the c-fos gene were also induced by stretching cardiac myocytes of both types of mice. An AT1 antagonist attenuated stretch-induced activation of ERKs in WT cardiomyocytes but not in KO cardiomyocytes. Down-regulation of protein kinase C inhibited stretch-induced ERK activation in WT cardiomyocytes, whereas a broad spectrum tyrosine kinase inhibitor (genistein) and selective inhibitors of epidermal growth factor receptor (tyrphostin, AG1478, and B42) suppressed stretch-induced activation of ERKs in KO cardiac myocytes. Epidermal growth factor receptor was phosphorylated at tyrosine residues by stretching cardiac myocytes of KO mice. These results suggest that mechanical stretch could evoke hypertrophic responses in cardiac myocytes that lack the AT1 signaling pathway possibly through tyrosine kinase activation.

Long-term effects of delapril hydrochloride on procollagen type III amino-terminal peptide, left ventricular mass and left ventricular function in hypertensive patients.

The long-term effect of delapril hydrochloride, a non-sulfhydryl angiotensin converting enzyme inhibitor, on serum concentrations of procollagen type III amino-terminal peptide (PIIIP) and left ventricular mass (LVM) and function were investigated in 15 hypertensive patients. Patients were treated with delapril hydrochloride 30 mg/day po for 12 months. Blood samples and an echocardiogram were obtained before treatment and after 6 and 12 months of treatment. Blood pressure, PIIIP, and LVM significantly decreased associated with an increase in left ventricular fractional shortening and mean systolic and diastolic posterior wall velocity at 6 and 12 months of treatment. Positive correlations between PIIIP and LVM (r=0.49, p<0.005) and negative correlations between PIIIP and left ventricular fractional shortening (r=-0.31, p<0.05) were found. Delapril hydrochloride reduced PIIIP and LVM and improved cardiac function in hypertensive patients.

Short-term and long-term effects of low-density lipoprotein (LDL) apheresis on restenosis after percutaneous transluminal coronary angioplasty (PTCA): is lowering Lp(a) by LDL apheresis effective on restenosis after PTCA?

It has been reported that serum lipoprotein(a) (Lp[a]) levels in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA) were significantly higher than in patients without restenosis. In this study, we evaluated the preventive effect of LDL apheresis on restenosis after PTCA in patients with hypercholesterolemia. For 10 patients who had shown a serum cholesterol level of more than 220 mg/dl despite treatment with antihypercholesterolemic drugs, LDL apheresis was conducted every 2 weeks after a successful PTCA until restenosis could be checked. In 4 patients, LDL apheresis was conducted for 2 years. LDL apheresis significantly reduced serum cholesterol from 248 +/- 22 mg/dl to 135 +/- 26 mg/dl and Lp(a) from 42 +/- 34 mg/dl to 21 +/- 16 mg/dl. The average degree of stenosis in the 11 lesions undergoing PTCA was 92 +/- 6% before PTCA, 35 +/- 10% immediately after PTCA, and 38 +/- 19% at 3 to 4 months after PTCA. Restenosis was observed in only 1 lesion. In 4 patients who received LDL apheresis for 2 years, restenosis did not occur in any of the 4 lesions treated. We concluded that LDL apheresis was an efficacious therapy to prevent restenosis after PTCA in patients with hypercholesterolemia.

Coronary calcification and coronary atherosclerosis: site by site comparative morphologic study of electron beam computed tomography and coronary angiography.

OBJECTIVES: We compared, on a site by site basis, the morphologic features of coronary calcifications determined by electron beam computed tomography (EBCT) and angiographically defined coronary atherosclerosis. BACKGROUND: Quantification of coronary calcification using EBCT is clinically useful for the prediction of coronary stenosis. However, the relation between calcification and angiographic findings has not been evaluated by site. METHODS: We studied 251 consecutive patients who underwent elective coronary angiography for suspected coronary artery disease by EBCT and analyzed findings by site. Coronary calcifications were classified according to their length and width versus the diameter of the coronary artery in which the calcification was observed as: none, spotty, long, wide and diffuse. RESULTS: Coronary calcifications were found in 666 (27%) of 2,470 segments. The positive predictive value (PPV) of coronary calcification for significant stenosis (> or = 75% densitometric narrowing) and for all angiographically detectable atherosclerotic lesions in a segment was 0.36 and 0.80, respectively. The PPV for significant stenosis and all atherosclerotic lesions was 0.04 and 0.17 in none, 0.18 and 0.59 in spotty, 0.32 and 0.87 in long, 0.40 and 0.84 in wide and 0.56 and 0.96 in diffuse calcifications, respectively. The PPV for both significant stenosis and all lesions differed significantly (p = 0.001) among the morphologic groups. Of the 105 eccentric significant stenoses, 54 (53%) were classified as long or diffuse calcifications. Of the 95 significant stenoses with multiple irregularities, 61 (64%) showed diffuse calcification. CONCLUSIONS: Morphologic evaluation of coronary calcifications using EBCT improved the prediction of coronary stenosis on a site by site basis and provided information related to angiographic morphology.

Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits.

An experimental model of early-stage cardiomyopathy was created by immunizing rabbits for 1 year with synthetic peptides corresponding to the sequence of the second extracellular loop of either beta-adrenoceptors or M2-muscarinic receptors. Thirty male rabbits were used and divided into three groups: a control group (n = 10), a group immunized with the peptide corresponding to the beta-adrenoceptor (beta 1 group) (n = 10) and a group immunized with the peptide corresponding to the M2-muscarinic receptor (M2 group) (n = 10). If the sera from both groups of immunized rabbits high-titres of anti-peptide antibodies were found throughout the study period but not in the sera from control rabbits or in the preimmune sera of immunized rabbits. No significant cross-reaction with peptides other than those used for immunization was found. The myocardial receptor density of both immunized groups displayed a strong trend toward receptor up-regulation. This was significant in the beta 1 group but not in the M2 group. Both groups of immunized rabbits displayed significantly enlarged ventricles and thinner walls, as compared with the control group. However, in contrast to the beta 1 group, which showed enlarged cavities in both left and right ventricles, the M2 group was mainly affected in the right ventricles. Moreover, morphological examinations of the hearts of rabbits from both immunized groups demonstrated focal myofibrillar lysis, loss of myofilament, mitochondrial swelling and condensation, sarcoplasmic vacuolation, deposition of dense granules in the sarcoplasm and the myofibrils. One of the sex control rabbit hearts which were examined showed mild degenerative changes in the myocardium and scant mononuclear cell infiltration. However, when all the control rabbit hearts were examined by electron microscopy, no significant alterations were found. These results suggest that immunization by peptides, corresponding to the target sequences for anti-receptor autoantibodies in idiopathic dilated cardiomyopathy, induces morphological changes in the heart similar to those found in the human disease.

Angiotensin II stimulates c-Jun NH2-terminal kinase in cultured cardiac myocytes of neonatal rats.

Many lines of evidence have suggested that angiotensin II (Ang II)plays an important role in cardiac hypertrophy. Ang II not only increases protein synthesis but also induces the reprogramming of gene expression in cultured cardiac myocytes. In the present study, to elucidate the mechanism by which Ang II regulates gene expression in cardiac myocytes, we examined whether Ang II activates c-Jun NH2-terminal kinase (JNK), which is a member of the mitogen-activated protein kinase family and activates the transcription factor, activator protein-1 (AP-1). The activity of JNK increased 5 minutes after the addition of Ang II, peaked at 20 minutes, and gradually decreased thereafter. Examination of the Ang II dose-response relation revealed detectable JNK activation at 10(-9) mol/L and maximal activation at 10(-6) mol/L. Ang II activated JNK through the AT1 receptor, and the activation was attenuated by the downregulation of protein kinase C or the chelation of intracellular Ca2+. Although the addition of either Ca2+ ionophore or phorbol ester resulted in little or no activation of JNK, simultaneous addition of both Ca2+ ionophore and phorbol ester markedly activated JNK. Slight expressions of the c-jun gene were observed in unstimulated cardiac myocytes, and Ang II increased expressions of the c-jun gene as well as the c-fos gene. Ang II increased transcription of the endothelin-1 gene through the AP-1 binding site. In conclusion, Ang II may activate JNK in cultured cardiac myocytes through an increase in intracellular Ca2+ and activation of protein kinase C, and the activated JNK may regulate gene expression by activating AP-1 during Ang II-induced cardiac hypertrophy.