Tomoaki Ohtsuka

Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy.

OBJECTIVES This study was designed to evaluate the beneficial effect of beta-blockers on circulating cytokine levels in patients with dilated cardiomyopathy (DCM). BACKGROUND Elevated circulating levels of inflammatory cytokines have been reported in patients with DCM. However, alterations of the levels of inflammatory and anti-inflammatory cytokines in association with beta-blocker therapy are unknown. METHODS We studied 32 patients with idiopathic DCM who had been treated with digitalis, diuretics and angiotensin-converting enzyme inhibitors. In addition to this combination therapy, beta-blockers were started in all patients. Serum levels of interleukin (IL)-10, tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNF-R1 and R2) were measured at baseline and 12 weeks after the initiation of beta-blocker therapy. We also measured plasma levels of neurohumoral factors, as well as left ventricular (LV) size and function. Ten age-matched subjects with no cardiac disease served as the control group. RESULTS Baseline levels of IL-10, TNF-alpha and sTNF-R2 were significantly higher in patients with DCM than in control subjects (p < 0.05). There was a significant positive correlation between IL-10 and TNF-alpha levels (r = 0.545, p = 0.029). The TNF-alpha/IL-10 ratio correlated well with plasma epinephrine levels (r = 0.677, p = 0.025), and the level of sTNF-R2 was closely related to LV size. Serum levels of IL-10, TNF-alpha and sTNF-R2 were significantly decreased during beta-blocker therapy (p < 0.005). CONCLUSIONS Our findings indicate that beta-blockers have an important immunoregulatory role in modifying the dysregulated cytokine network in DCM. This effect of beta-blockers may be partly responsible for the efficacy of therapeutic drugs for heart failure.

Possible link between large artery stiffness and coronary flow velocity reserve

Background: Population studies have shown that increased large artery stiffness is an independent predictor of cardiovascular events. Experimental studies have shown that a stiff aorta is associated with decreased coronary blood flow. However, a link between large artery stiffness and coronary microvascular function in the clinical setting has not been demonstrated previously. Objective: To evaluate the relationship between large artery stiffness and coronary flow velocity reserve (CFVR). Patients and methods: 102 consecutive subjects (mean (SD) age 62 (10) years) without coronary and peripheral arterial disease were enrolled in the study. After 15 minutes’ rest, measurements were obtained of brachial-ankle pulse wave velocity (baPWV), augmentation index (AIx) from a carotid pulse tracing, and transthoracic echocardiographic measures, including coronary flow velocity in the left anterior descending coronary artery. In addition, coronary flow velocity during hyperaemia was measured during an intravenous infusion of adenosine triphosphate. CFVR was defined as the ratio of hyperaemic to basal coronary velocity. Results: Subjects with decreased CFVR (<2.5; n = 40) had significantly higher baPWV (1848 (369) cm/s vs 1548 (333) cm/s; p<0.001), greater AIx (25.3 (11.0)% vs 16.3 (20.0)%; p = 0.01) and greater pulse pressure (PP) (64 (13) mm Hg vs 54 (13) mm Hg; p<0.001) than those with normal CFVR (⩾2.5; n = 62). Multivariate analysis showed that AIx and PP were independent predictors of CFVR (r =  −0.32, p<0.001 and −0.25, p = 0.02, respectively). Conclusions: The data suggest that large artery stiffening is linked to a reduction of CFVR, which may partially explain the higher cardiac event rate in patients with increased large artery stiffness.

Left Ventricular Geometry as an Independent Predictor for Extracardiac Target Organ Damage in Essential Hypertension

Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. It has not been established, however, whether left ventricular geometry is an independent predictor of extracardiac target organ damage in essential hypertension. Study groups were classified according to relative wall thickness: 27 patients with concentric LVH and 50 patients with eccentric LVH. Age and left ventricular mass indexes of two groups were matched. As indexes of extracardiac target organ damage, retinal funduscopic grade, and serum creatinine level were measured. The severity of hypertensive retinopathy and the renal involvement were more severe in patients with concentric LVH than in patients with eccentric LVH. Extracardiac target organ damage was consistently higher in patients with concentric LVH than in those with eccentric LVH. Systemic hemodynamics paralleled ventricular geometric patterns, with higher peripheral resistance and lower aortic compliance in patients with concentric LVH, whereas end-diastolic volumes and stroke volumes were higher in patients with eccentric LVH than in patients with concentric LVH. In addition, total peripheral resistance was related to retinal fundoscopic grade (r = 0.41, P < .01), and serum creatinine level (r = 0.28, P < .05). Even in the presence of an identical degree of LVH, echocardiographically determined left ventricular geometry may provide a further independent stratification of extracardiac target organ damage in essential hypertension.

Determinants of left ventricular untwisting behaviour in patients with dilated cardiomyopathy: analysis by two-dimensional speckle tracking

Background/objective: Left ventricular (LV) untwisting velocity has emerged as a novel index of LV diastolic function since it is thought to be related to LV diastolic suction. However, the pathophysiology of LV untwisting behavior has not been fully investigated. The aim of this study was to investigate the determinants of LV peak untwisting velocity in patients with dilated cardiomyopathy (DCM). Methods: 101 patients with DCM (mean age 60 (SD 13) years) and 50 control subjects were evaluated. After a standard echocardiographic examination, peak torsion and peak untwisting velocity were measured using two-dimensional speckle-tracking imaging. Radial dyssynchrony was assessed by speckle-tracking radial strain analysis. Tissue Doppler derived systolic (Ts-SD) and diastolic (Te-SD) dyssynchrony indices were also assessed. Results: The patients with DCM had significantly smaller peak torsion (p<0.001) and peak untwisting velocity (p<0.001) and greater radial dyssynchrony (p<0.001) and Ts-SD (p<0.001) and Te-SD (p = 0.001) compared with the control subjects. The peak untwisting velocity was correlated with end-systolic volume index (r = 0.524, p<0.001), E/e′ (r = 0.365, p<0.001), radial dyssynchrony (r = 0.578, p<0.001), Ts-SD (p<0.001), Te-SD (p<0.001) and peak torsion (r = −0.635, p<0.001) in patients with DCM. Multivariate analysis revealed that peak torsion, radial dyssynchrony and E/e′ were independent predictors of peak untwisting velocity in patients with DCM (standard coefficient −0.483, p<0.001, 0.330, p<0.001 and 0.241, p = 0.001, respectively). Conclusion: These results suggest that strain-based LV radial dyssynchrony and E/e′ as well as LV torsion are related to diastolic untwisting behaviour in patients with DCM.

Neurogenic Stunned Myocardium

A74-year-old woman was admitted for evaluation of chest pain. She had fallen and hit her head 4 days before her admission and had lost consciousness. Her chest pain had begun immediately after this event. An ECG on admission revealed abnormal Q waves and ST-segment elevation (Figure 1A⇓). Her plasma creatine phosphokinase level was significantly elevated (386 IU/L), with an increase in MB isozyme level on admission. …

Clinical implications of circulating soluble Fas and Fas ligand in patients with acute myocardial infarction.

BACKGROUND Apoptotic cell death is the major form of myocardial damage produced by coronary ischemic events. OBJECTIVE To assess whether circulating levels of soluble Fas (sFas), an inhibitor of apoptosis, and sFas ligand, an inducer of apoptosis, in patients with coronary artery disease are greater than normal. METHODS Forty-seven patients [acute myocardial infarction (AMI) in 17, old myocardial infarction (OMI) in 15, stable angina in 15] and 10 normal control subjects participated in this study. Serum levels of sFas and sFas ligand in all patients were measured, and cardiac catheterizations were performed. RESULTS Serum levels of sFas were greater than normal only in patients with AMI (4.6 +/- 1.6 ng/ml); the levels were significantly higher than those in patients with OMI (2.1 +/- 0.6 ng/ml) and stable angina (2.2 +/- 0.5 ng/ml), and in normal subjects (2.0 +/- 0.6 ng/ml; P < 0.0001). However, there was no difference among serum levels of sFas ligand for all groups. For patients with AMI, there was no significant correlation between serum levels of sFas and peak levels both of plasma creatine phosphokinase and of plasma myosin light chain type I as clinical indexes of infarct size. However, there were significant correlations between serum levels of sFas and both pulmonary artery wedge pressure (r = 0.767, P = 0.0003) and left ventricular end-diastolic pressure (r = 0.629, P = 0.03). CONCLUSIONS Circulating sFas increases in concentration in relation to the severity of hemodynamic conditions in patients with AMI, but it is independent from size of infarct. Therefore, circulating sFas could play an important role as the marker of pathophysiologic conditions associated with cardiomyocyte apoptosis in AMI.

Serum levels of matrix metalloproteinases and tumor necrosis factor-α in patients with idiopathic dilated cardiomyopathy and effect of carvedilol on these levels

I myocardial matrix metalloproteinase (MMP) activity has been reported to occur in clinical and experimental forms of dilated cardiomyopathy.1–3 Proinflammatory cytokines, such as tumor necrosis factor(TNF), are important regulators of MMP gene expression. Previous experimental studies have shown that TNFstimulates myocardial MMP activity and can lead to degradation of the extracellular matrix in the myocardium.4 However, few clinical studies of the relation between circulating MMP and TNFlevels in idiopathic dilated cardiomyopathy (IDC) have been conducted. Recently, we reported the presence of increased circulating TNFin patients with IDC, and that blockers could reduce the increased circulating TNFlevels in IDC.5,6 The present study further clarifies the relation between circulating levels of MMPs and TNFin patients with IDC. • • • We studied 34 consecutive patients with IDC between January 1999 and December 2001. The diagnosis of IDC was based on patient history, physical examination, electrocardiogram, echocardiogram, and cardiac catheterization. All patients underwent coronary angiography during the study period, and patients with epicardial coronary artery disease were excluded. Patients who had clinical or laboratory evidence of infections, neoplasms, autoimmune disease, or liver or renal dysfunction were also excluded from this study. Ten age-matched subjects who had no evidence of organic cardiac disease and no cardiac dysfunction were retrospectively selected as the control group. All subjects participated in this study after giving informed consent, and the protocol was approved by the Human Investigations Committee of our institution. In 20 patients who were poor responders to treatment with angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers for 6 months, carvedilol, a nonselective blocker, was administered orally in addition to combination therapy after their hospital admission. In 18 patients with New York Heart Association functional class II or III congestive heart failure, the initial dosage was 2.5 mg twice daily; the doses were increased at weekly intervals for 8 weeks. In 2 patients in New York Heart Association functional class IV, the initial dosage was 1.0 mg twice daily; the doses were increased at weekly intervals for 12 weeks. The target dose was 25 mg/day, considering the weight of patients in this study of 75 kg. If a decrease in systolic blood pressure to 90 mm Hg or a decrease in heart rate at rest to 60 beats/min occurred, increments in dose were discontinued. As a result, the mean final dose of carvedilol was 19.2 mg. Maintenance of final doses was continued for an additional 6 months. Blood samples from patients were collected for measurement before and 6 months after initiation of carvedilol therapy. After bed rest for 30 minutes, peripheral venous blood samples were collected into chilled tubes and immediately centrifuged at 4°C. The serum samples were stored at 80°C until assay. Serum levels of TNFwere measured by enzyme-linked immunosorFrom The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime, Japan. Dr. Ohtsuka’s address is: The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 7910295, Japan. E-mail: tohtsuka@m.ehime-u.ac.jp. Manuscript received October 24, 2002; revised manuscript received and accepted December 30, 2002. FIGURE 1. Serum levels of TNF, MMP-1, MMP-3, and MMP-9 in 10 age-matched normal control subjects (NC) and in 34 patients with IDC. *p <0.05; **p <0.001 versus control subjects.

Right Ventricular Pacing from the Septum Avoids the Acute Exacerbation in Left Ventricular Dyssynchrony and Torsional Behavior Seen with Pacing from the Apex

OBJECTIVE The study objective was to compare the left ventricular (LV) dyssynchrony and torsional behavior between right ventricular apical (RVA) and right ventricular septal (RVS) pacing. METHODS Forty-six patients with symptomatic sick sinus syndrome and preserved LV function were assigned to 2 groups: RVA (n = 23) and RVS (n = 23). Echocardiographic study including two-dimensional speckle tracking imaging was performed in the AAI and DDD modes. RESULTS Mean QRS width during DDD mode was significantly longer with RVA pacing than with RVS pacing. Dyssynchrony, torsion, and untwisting rate during DDD mode were significantly worse with RVA than with RVS pacing. In patients with RVA pacing, there was an increase in longitudinal dyssynchrony from AAI to DDD mode that significantly correlated with the deterioration of untwisting rate. CONCLUSION In bradyarrhythmic patients with preserved LV function, RVS pacing resulted in a reduced LV dyssynchrony and better torsional behavior than RVA pacing.

Sex-related differences in the relations of insulin resistance and obesity to left ventricular hypertrophy in Japanese hypertensive patients.

Echocardiographically determined left ventricular (LV) hypertrophy is a powerful, independent predictor of cardiovascular morbidity and mortality. Both insulin resistance and obesity have a well-known association with LV hypertrophy. However, whether or not there are sex-related differences in the relations of insulin resistance and obesity to LV hypertrophy has never been systematically explored in Japan. We enrolled 91 never-treated hypertensive patients (49 men and 42 women) to assess the possible relations of insulin resistance and obesity to LV geometry. Insulin resistance was estimated using the homeostasis model assessment (HOMA) formula. Echocardiographically determined LV mass and relative wall thickness were measured as markers of LV geometry. In addition, body mass index (BMI) was calculated as weight (kg) divided by height (m)2 as a marker of obesity. Independent determinants of LV mass in male hypertensive patients were HOMA value (p<0.0001) and age (p=0.034). BMI did not bear a significant relation to LV mass. In comparison, in female hypertensive patients BMI was an independent determinant of LV mass (p=0.011). The HOMA value did not bear a significant relation to LV mass in the female hypertensive patients. In conclusion, these findings indicate the presence of sex-related differences in the relations of insulin resistance and obesity to LV hypertrophy in Japanese hypertensive patients. The effect of obesity on LV geometry was greater in female hypertensive patients than in male hypertensive patients.

The differences in left ventricular torsional behavior between patients with hypertrophic cardiomyopathy and hypertensive heart disease.

BACKGROUND The aim of this study was to investigate the differences in left ventricular (LV) twisting behavior between patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD). METHODS Forty-four patients with HCM (mean age, 63±15 years), 35 patients with HHD (mean age, 63±13 years) and 20 age and sex-matched control subjects were evaluated. After a standard echocardiographic examination, LV twist and twisting velocity profiles from apical and basal short-axis images were analyzed using two-dimensional speckle tracking imaging. RESULTS LV diastolic and systolic dimensions, and ejection fraction were not significantly different among the groups. LV mass index and early diastolic mitral annular velocity were not significantly different between the HCM and HHD groups. The peak torsion in the HCM and HHD groups was significantly greater than that in the control group. The peak untwisting velocity in the HCM group was comparable with that in the control group. However, when the peak untwisting velocity was corrected by peak torsion, this ratio was significantly decreased in the HCM group compared with the values in the HHD and control groups. The time to peak untwisting velocity in the HCM group was significantly longer than the values in the HHD and control groups. CONCLUSIONS These results suggest that enhanced peak torsion in HCM may improve untwisting behavior, but this mechanism fails to fully compensate for impaired untwisting behavior compared with HHD.