Clonazepam-associated Bradycardia in a Disabled Elderly Woman with Multiple Complications.

We herein report an 87-year-old woman who was taking clonazepam at 1.5 mg/day. She was hospitalized with an old cerebral infarction complicated with symptomatic epilepsy, dementia, dyslipidemia, and chronic cholecystitis. Electrocardiogram revealed severe bradycardia at 31 beats/min. The bradycardia disappeared on day 3 after clonazepam withdrawal, although the serum clonazepam level had been within normal limits. She was diagnosed with clonazepam-associated bradycardia, which was likely related to the potential calcium channel-blocking properties of clonazepam. Because of age-related pharmacokinetic and pharmacodynamic changes, the adverse effects of clonazepam should be considered, especially in disabled elderly individuals with multiple comorbidities.

The waveform index of the ophthalmic artery predicts impaired coronary flow reserve.

BACKGROUND: Coronary flow reserve (CFR) can decrease with impairment in coronary microcirculation, even in the absence of epicardial conduit obstruction. Recently, the ophthalmic artery (OA), which is the first major branch of the internal carotid artery and is representative of microarterioles, has been identified using color Doppler sonography. However, the features of ultrasound waveform indices suggestive of impaired OA microcirculation and the relationships between these indices and CFR have not been elucidated. The present study aimed to assess the features of ultrasound waveform indices suggestive of impaired OA microcirculation and the relationships between these indices and CFR. METHODS AND RESULTS: A total of 30 consecutive patients with a normal coronary angiogram and normal left ventricular function were studied. Patients with ≥ 25% stenosis of the right common or internal carotid artery were excluded. The CFR was defined as the ratio of adenosine-induced hyperemic to baseline blood flow velocity with an intracoronary Doppler guidewire. Color Doppler imaging was used to determine the blood flow velocity of the right OA, and the indices of peripheral resistance (resistance index [RI], pulsatility index [PI], and systolic mean velocity to diastolic mean velocity [Sm/Dm] ratio) were calculated. The ultrasound form showed a distinctive biphasic wave during systole followed by a monophasic wave during diastole. The velocity component in the early-systolic wave was higher than that in the mid-systolic wave or the diastolic wave (31.4 ± 5.1 vs. 26.1 ± 5.4 vs. 15.9 ± 4.0 cm/s, P<0.0001). The RI and PI were not related to the CFR, and the Sm/Dm ratio was negatively correlated with the CFR (ß=-0.415, P=0.022). However, the relationship was attenuated by clinical variables closely associated with the Sm/Dm ratio or CFR, and hemoglobin A1c was a common mediator. The best Sm/Dm ratio cutoff for predicting an impaired CFR was 2.5 based on a receiver operating characteristic curve analysis. CONCLUSIONS: An increase in the Sm/Dm ratio, which reflects a characteristic waveform, indicates impaired OA microcirculation. The ratio is negatively correlated with CFR, and therefore, it may be applied for the noninvasive evaluation of coronary physiology. Furthermore, hemoglobin A1c may be a common mediator for the OA and coronary microcirculation.

[A ten-year follow-up of a 109-year-old woman with myocardial infarction].

A 109-year-old woman was hospitalized with myocardial infarction in the geriatric long-term care ward of our hospital. Her medical history was unknown, and she was receiving only peroral 20 mg/day furosemide. Her medical records at another hospital revealed that she had been given a previous diagnosis of myocardial infarction of the anteroseptal wall of the left ventricle by a cardiovascular specialist approximately 10 years previously. Although treatment with cardiovascular drugs such as an angiotensin II receptor blocker, aspirin, and spironolactone had been started, it was discontinued because of her hospital transfer and change in her attending physician. Because of aggravation of the symptoms of cardiac failure caused by infection, treatment with the angiotensin-converting enzyme inhibitor temocapril (1 mg/day), spironolactone (12.5 mg/day), aspirin (100 mg/day), and a beta-adrenoceptor blocker carvedilol (2 mg/day) was tentatively initiated. Consequently, her B-type natriuretic peptide (BNP) level improved and her condition stabilized. She finally died of old age. Both inappropriate sharing of patient information among medical facilities and restrictions on medical care in Japanese health care system for the elderly may lead to improper and/or inadequate medical treatment for elderly patients. Although little evidence is available to support medical care for centenarians, treatment which is based on a thorough understanding of their physiological characteristics enables us to improve their quality of life.

Hypercholesterolemia and hypoadiponectinemia are associated with necrotic core-rich coronary plaque.

BACKGROUND: Hypercholesterolemia is a risk factor for coronary artery disease and closely linked to unstable plaque. Hypoadiponectinemia is frequently observed in patients with metabolic syndrome complicated with macroangiopathy and predicts poor clinical outcome. Spectral analysis of intravascular ultrasonography radiofrequency (IVUS-Virtual Histology [VH]) allows quantitative analysis of plaque composition. The purpose of this study was to verify the effects of low-density lipoprotein (LDL) cholesterol level on plaque morphology, and test the hypothesis that adiponectin influences coronary plaque volume and composition. METHODS: Preintervention IVUS-VH using a continuous pullback was performed in 92 coronary vessels in 92 patients with coronary artery disease. The morphological distribution of plaque was evaluated prospectively in a 60-mm segment of coronary vessels containing the culprit lesion. RESULTS: Serum LDL cholesterol levels correlated positively with necrotic core volume (r = 0.217, P = 0.037) and percent necrotic core tissue (r = 0.308, P = 0.003), while plasma adiponectin levels correlated negatively with plaque volume (r = -0.297, P = 0.004) and necrotic core volume (r = -0.306, P = 0.003). Multiple regression analyses showed close association between necrotic core volume and statin-use (ß = -21.68, P = 0.004) and adiponectin levels (ß = -31.25, P = 0.038), and that percent necrotic core tissue was influenced by statin-use (ß = -4.595, P = 0.026) and LDL cholesterol levels (ß = 0.092, P = 0.031). CONCLUSIONS: Adiponectin is closely linked to coronary plaque volume. Hypercholesterolemia and hypoadiponectinemia correlate with necrotic core lesions and may contribute to increased risk of coronary plaque vulnerability. Statins can affectively prevent necrotic core plaque formation associated with hypercholesterolemia and hypoadiponectinemia.

Waveform of ophthalmic artery Doppler flow predicts the severity of systemic atherosclerosis.

BACKGROUND: Doppler imaging of ophthalmic artery (OA), the first major branch of the internal carotid artery, provides anatomical advantages due to the vertical angle to the body surface and absence of ultrasonic obstacles. It was hypothesized that the Doppler waveform indices of OA correlate with severity of systemic atherosclerosis. METHODS AND RESULTS: The study subjects were 180 patients who underwent cardiac catheterization and OA Doppler imaging (90 patients with coronary artery disease (CAD) and 90 control patients). The ratio of stroke volume to pulse pressure, an index of arterial compliance, was closely associated with the ratio of systolic to diastolic mean velocity (Sm/Dm) in OA. The level of Sm/Dm increased in proportion with the increase in number of stenosed coronary arteries (0-vessel disease 2.1+/-0.3, 1-vessel disease 2.3+/-0.3, multi-vessel disease 2.6+/-0.5, P<0.0001). The Sm/Dm level in OA correlated positively with age, pulse pressure, pulse wave velocity, resistive index and pulsatility index in OA. The best Sm/Dm cut-off to predict CAD was 2.3, and patients with Sm/Dm >2.3 had 8.0-fold risk for CAD. CONCLUSIONS: The waveform indices of OA are clinically useful for evaluating the severity of CAD and may help explain the missing link between OA circulation and systemic arterial compliance.

Smoking cessation is associated with increased plasma adiponectin levels in men.

OBJECTIVES: Low levels of adiponectin, an adipocytokine with anti-diabetic and anti-atherogenic properties, are associated with increased risk of future myocardial infarction in men. Previous studies have demonstrated that cigarette smoking is involved in the development of insulin resistance, and current smokers have been shown to have reduced plasma adiponectin levels. However, the influence of smoking cessation on adiponectin levels remains unknown. We sought to assess whether smoking cessation is associated with increased plasma adiponectin levels in men. METHODS: The study includes 72 men (47 non-smokers and 25 current smokers at baseline) with stable angina pectoris who underwent percutaneous coronary intervention and follow-up coronary angiography 6 months later. During the 6-month follow-up period, all 47 non-smokers remained non-smokers, while 15 men of the 25 baseline current smokers successfully quit smoking. We evaluated plasma adiponectin levels at coronary intervention and 6 months later. RESULTS: Plasma adiponectin levels at coronary intervention were comparable to those after 6 months in non-smokers (4.22 [3.15-6.43] vs. 4.58 [3.03-6.26] microg/mL, P=0.124) and in persistent smokers (4.77 [4.25-10.53] vs. 5.16 [4.11-8.10] microg/mL, P=0.721). Meanwhile, an increase in adiponectin level was observed in patients who quit smoking for 6 months (4.24 [3.30-5.70] vs. 5.50 [4.03-8.00] microg/mL, P=0.002). Univariate analysis revealed that the percent increase in adiponectin levels correlated positively with smoking cessation (P=0.003) and negatively with additional use of beta-blockers (P=0.049). In addition, increases in adiponectin levels were closely associated with increase in high-density lipoprotein cholesterol (P=0.148), decrease in triglycerides (P=0.140), and additional use of renin-angiotensin system inhibitors (P=0.069). Multivariate analysis demonstrated that smoking cessation was an independent determinant of the increase in adiponectin (P=0.036). CONCLUSIONS: Smoking cessation is associated with increased plasma adiponectin levels in men with stable angina, suggesting that the significance of smoking cessation may be partly explained by the increase in adiponectin level.

Hypoadiponectinemia is associated with impaired glucose tolerance and coronary artery disease in non-diabetic men.

BACKGROUND: Impaired glucose tolerance (IGT) is a significant risk factor for cardiovascular disease, but is not always recognized in the clinical setting. An anti-atherogenic adipocytokine, adiponectin, is decreased in type 2 diabetes mellitus, but its role in non-diabetic subjects has not been clarified. The hypothesis investigated in the present study was that plasma adiponectin levels correlate with IGT and coronary artery disease (CAD) in non-diabetic men. METHODS AND RESULTS: Glucose intolerance was evaluated by an oral glucose tolerance test and plasma adiponectin levels were measured in 232 non-diabetic men who underwent coronary angiography. Patients with IGT (n=102) had significantly lower adiponectin levels than those with normal glucose tolerance (n=130) (4.47 [3.23-6.39] vs 5.85 [3.99-8.65] mug/ml, p=0.003). Plasma adiponectin levels were associated with IGT in multiple logistic regression analysis (odds ratio (OR) 0.623, 95% confidence interval (CI) 0.397-0.980; p=0.041). Non-diabetic patients with CAD (n=122) had lower adiponectin levels than those without CAD (n=110) (4.60 [3.32-6.38] vs 6.08 [4.10-9.88] microg/ml, p<0.001). Multiple logistic regression analysis demonstrated adiponectin independently correlated with the presence of CAD (OR 0.432, 95% CI 0.256-0.728; p=0.002). CONCLUSIONS: Hypoadiponectinemia is associated with IGT and CAD in non-diabetic men, suggesting that the adiponectin level can provide valuable information regarding the risk of CAD even in non-diabetic subjects.

Future adverse cardiac events can be predicted by persistently low plasma adiponectin concentrations in men and marked reductions of adiponectin in women after acute myocardial infarction.

There is conflicting information about whether mortality after AMI is higher in women than men. We investigated the significance of plasma adiponectin concentrations on major adverse cardiac events (MACE) after acute myocardial infarction (AMI) to delineate any differences between men and women. The study patients consisted of 114 men and 42 women with AMI. The incidence of MACE was significantly higher in women than men during the entire follow-up period (p<0.05). Compared with men for post-AMI MACE, the hazard ratio for women was 5.6 after adjustment for prognostic factors. Killip class (p<0.001) and sex differences (p<0.05) were independent predictors of MACE at 1 year post-AMI. Plasma adiponectin levels in women were significantly higher than men on admission (8.66 microg/mL [range: 6.6-14.08] versus 4.71 microg/mL [range: 3.47-7.27], p<0.0001) and during the post-AMI course (all p<0.0001). Multivariate analysis identified plasma adiponectin level on admission as an independent predictor of MACE in men (p<0.001) and the difference between plasma adiponectin levels at discharge and on admission in women (p<0.05). Patterns of serial changes in plasma adiponectin concentrations are different between men and women and plasma adiponectin concentrations can be used to predict future adverse cardiac events in AMI patients.

Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease.

Reduced incidence of type-2 diabetes has been shown in patients treated with pravastatin. Adiponectin can exhibit beneficial effects on glucose metabolism. We investigated whether pravastatin could improve glucose tolerance associated with increasing adiponectin levels in patients with impaired glucose tolerance (IGT). This study consisted of 40 coronary artery disease (CAD) patients with IGT assessed by oral glucose tolerance test (OGTT). Patients were randomized to receive pravastatin (n=20) or no lipid-lowering medications (control group, n=20) for 6 months, after which OGTT was repeated and adiponectin levels were measured. Pravastatin treatment significantly decreased levels of total cholesterol (16%), low-density lipoprotein cholesterol (23%) and high-sensitivity C-reactive protein (37%) (p<0.01, respectively). At 2h in OGTT, pravastatin significantly improved hyperglycemia (-14%) and hyperinsulinemia (-23%). Pravastatin treatment significantly elevated plasma adiponectin levels (35%; p<0.001) but not in the control group. The glucose reduction at 2h post-OGTT was significantly associated with increased levels of adiponectin (r=-0.462; p=0.003). Pravastatin treatment is an independent predictor for improvement of post-loaded hyperglycemia (odds ratio; 5.7; 95% confidence interval 1.7-19.3; p=0.003) and achieved beneficial conversion from IGT to normal glucose tolerance (40%; p=0.03). Pravastatin exhibits beneficial effects on glucose metabolism especially in the postprandial state associated with increasing plasma adiponectin levels in CAD patients with IGT.

Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease.

OBJECTIVES: We sought to assess whether plasma adiponectin levels correlate with angiographic coronary lesion complexity in patients with coronary artery disease (CAD). BACKGROUND: Metabolic disorders, including diabetes mellitus and metabolic syndrome, are important risk factors for acute cardiovascular events, and adiponectin is a key molecule of metabolic disorders, with anti-atherogenic properties. Low plasma adiponectin levels are associated with CAD and future incidence of myocardial infarction. The involvement of adiponectin in coronary plaque vulnerability, which may be reflected by angiographic complex lesions, remains to be elucidated. METHODS: We measured plasma adiponectin levels in 207 men (152 with stable CAD and 55 with acute coronary syndromes [ACS]). Coronary lesions were classified as of simple or complex appearance. RESULTS: Plasma adiponectin levels were significantly lower in stable CAD patients with complex coronary lesions (n = 60) than in those with simple lesions (n = 92) (4.14 [range 2.95 to 6.02] vs. 5.27 [range 3.67 to 8.12] microg/ml, p = 0.006). Multiple logistic regression analysis demonstrated that adiponectin level was independently associated with complex lesions (odds ratio 0.514, 95% confidence interval 0.278 to 0.951; p = 0.034). Polytomous logistic regression revealed that adiponectin correlated independently with both single and multiple complex lesions. Among patients with ACS, who had lower adiponectin levels than stable CAD patients, those with multiple complex lesions had significantly lower adiponectin than those with a single complex lesion (3.26 [range 2.26 to 4.46] vs. 4.21 [range 3.36 to 5.41] microg/ml, p = 0.032). CONCLUSIONS: Plasma adiponectin levels are significantly associated with coronary lesion complexity in men with CAD. Low adiponectin levels may contribute to coronary plaque vulnerability.

Hypoadiponectinemia is associated with coronary artery spasm in men.

BACKGROUND: The relationship between adiponectin and coronary spastic angina (CSA), both of which are closely involved in coronary endothelial dysfunction, has not been elucidated. METHODS AND RESULTS: Plasma adiponectin concentrations were examined in 55 men with CSA and 55 with chest pain syndrome (CPS). The plasma log-adiponectin levels were significantly lower in patients with CSA than with CPS (0.61+/-0.28 vs 0.80+/-0.21 microg/ml, p < 0.0001). The prevalence of smoking was significantly higher in the CSA patients than in those with CPS (50.9% vs 29.1%, p = 0.0195). In multiple logistic regression analysis, log-adiponectin (p = 0.0008) and smoking (p = 0.0210) were independent determinants of CSA. Conclusions Hypoadiponectinemia is a potential risk factor for CSA in men, independent of smoking.

Usefulness of preprocedural platelet aggregation to predict restenosis after percutaneous coronary intervention.

We investigated whether the assessment of small platelet aggregates before percutaneous coronary intervention (PCI) could predict restenosis after PCI. This was a prospective cohort study that enrolled 189 consecutive patients who had coronary artery disease. In multiple logistic regression analysis, higher levels of preprocedural small platelet aggregates were independently associated with restenosis after PCI. Measurement of small platelet aggregates may serve as a useful clinical variable for stratifying patients who present for PCI.

Levels of the adipocyte-derived plasma protein, adiponectin, have a close relationship with atheroma.

INTRODUCTION: Inflammation is a key process in atherosclerotic formation. Structural changes in the carotid arterial wall including detection of focal plaques are measured as the intima-media thickness (IMT) providing an index of atheroma. Coronary arterial plaques may be considered as vascular structural changes. Distensibility of the arteries can be assessed by functional changes in pulse wave velocity (PWV) providing an index of sclerosis. Adiponectin has potential antiatherosclerotic properties. We hypothesized that adiponectin was associated with atherosclerotic vascular changes involved in inflammation. MATERIALS AND METHODS: We enrolled 142 patients with coronary artery disease (CAD) and 108 control patients, matched for age, sex, and body mass index (BMI) with CAD patients. We investigated the relationship between adiponectin, C-reactive protein (CRP), and atherosclerotic vascular changes. RESULTS: CRP (p=0.0009), high-density lipoprotein cholesterol (HDL-C; p=0.02), and IMTmax (p=0.02) were determinants of adiponectin independent of glucose intolerance (p=0.0001), BMI (p=0.002), and CAD (p=0.03), all of which have been significantly associated with adiponectin (r=0.38). Adiponectin was not correlated with PWV. CRP, glucose intolerance, and HDL-C that correlated with adiponectin were inversely correlated with IMTmax and CAD. CRP was negatively correlated with HDL-C (r=-0.24, p=0.0002) and positively correlated with glucose intolerance (r=0.15, p=0.01). CONCLUSIONS: Adiponectin has a close relationship with CRP, IMTmax, CAD, HDL-C, and other established risk factors. CRP, glucose intolerance, and HDL-C are common mediators between adiponectin and atheromatous vascular changes, which are contrary to each other. The exacerbation of atherogenesis may be involved in a decrease of adiponectin through abnormal glyco- and lipid-metabolism by promoting inflammation.

Sensorineural hearing loss combined with Takayasu's arteritis.

A 49-year-old woman complained of hearing loss and diminution of left radial arterial pulsation. She had been diagnosed with sudden deafness and treated with corticosteroids. Her audibility deteriorated again after the cessation of the therapy. Angiograms showed stenosis in the bilateral carotid arteries, the left vertebral artery, the left subclavian artery, and the pulmonary arteries. She was diagnosed with Takayasu's arteritis. After steroid therapy was restarted, there were improvements in her audibility, radial arterial pulsation, and levels of inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, and gamma-globulin), fibrinogen, interleukin-6, and RANTES (regulated on activation, normal T cell expressed and secreted).

Adiponectin is inversely related to plasminogen activator inhibitor type 1 in patients with stable exertional angina.

Adipose tissue is a secretory organ producing a variety of bioactive substances, such as adiponectin. Adiponectin has antiatherogenic properties while plasminogen activator inhibitor type 1 (PAI-1) is closely involved in the development of atherosclerosis. The relationship between adiponectin and PAI-1 in patients with coronary artery disease (CAD) has not been clarified. This study examined plasma levels of adiponectin and PAI-1 in 64 patients with stable exertional angina (SEA) and 65 patients with the chest pain syndrome (CPS). Plasma log-adiponectin levels were significantly lower in patients with SEA (0.62+/-0.08 micro g/dL) compared to those with CPS (0.86+/-0.05 micro g/dL) (p<0.0001). The plasma levels of log-PAI-1 were significantly higher in patients with SEA (1.23+/-0.18 ng/mL) compared to those with CPS (1.15+/-0.22 ng/mL) (p<0.05). Plasma log-adiponectin levels correlated negatively with diabetes mellitus (DM), body mass index (BMI), log-PAI-1 (r=-0.284, p<0.001), triglyceride (TG), and remnant-like particles cholesterol (RLP-C), and positively with high-density lipoprotein cholesterol (HDL-C) levels. Plasma levels of log-PAI-1 correlated positively with DM, BMI,TG and RLP-C levels, and negatively with HDL-C levels. Multiple logistic regression analysis identified sex, angina pectoris, and PAI-1 as independent determinants of hyperadiponectinemia (p<0.05). Adiponectin is inversely related to PAI-1. DM, BMI,TG, HDL-C, and RLP-C are common mediators between adiponectin and PAI-1, and treatment for common mediators may prevent the development of CAD by reducing PAI-1 and increasing adiponectin levels.

Löffler's endocarditis associated with unusual ECG change mimicking posterior myocardial infarction.

A73-year-old man with a history of bronchial asthma and atrial fibrillation was admitted to our hospital because of dyspnea and back pain. Blood analysis revealed a marked increase in total blood cell and eosinophil counts. The creatine kinase and creatine kinase-MB increased slightly. The ECG demonstrated significant ST-segment depression that mimicked acute posterior myocardial infarction. Emergent coronary angiography showed no stenotic lesions. The histological findings in endomyocardial biopsy showed thickened endocardium associated with significant eosinophilic infiltration, which was compatible with Löffler's endocarditis. After the administration of prednisolone, the patient's general condition, eosinophilia, ECG abnormalities, and histological findings were improved dramatically. The endomyocardial biopsy in the acute phase was helpful for diagnosis and therapeutic decision-making.

[Intractable infective endocarditis associated with supraaortic stenosis in Williams syndrome: a case report].

A 17-year-old man with supravalvular aortic stenosis associated with Williams syndrome was admitted to our hospital for intensive treatment for intractable infective endocarditis. The patient had a history of percutaneous balloon valvuloplasty for aortic stenosis in 1992. He was well until late in 1999, when he had a high temperature after dental work-up. The diagnosis was infective endocarditis but antibiotic therapy was not effective. He was transferred to our clinic. Transthoracic echocardiography demonstrated bicuspid aortic valve, supraaortic stenosis, mitral valve prolapse with severe regurgitation and scattered vegetations on the anterior mitral and aortic valves. In addition, transesophageal echocardiography showed innumerable mobile vegetations located from Valsalva's sinus to the descending aorta. Aortic root and arch replacement with a homograft and mitral valve replacement with an artificial valve were successfully performed to eliminate the infective endocarditis. In the present patient, the flow jet across the supraaortic stenosis seemed to cause a predisposition to severe endocarditis.