Katsuhiko Hiramori

Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese.

BACKGROUND The angiotensin I-converting enzyme (ACE) is a key component of the renin-angiotensin system thought to be important in the pathogenesis of hypertension and cardiovascular disease. Deletion polymorphism in the ACE gene may be a risk factor for myocardial infarction in the Caucasian population. However, this finding has not yet been investigated in the Japanese population. METHODS AND RESULTS A 287-bp insertion/deletion polymorphism in intron 16 of the ACE gene was examined by polymerase chain reaction in a cross-sectional study of 100 healthy subjects and 178 patients with coronary artery disease (CAD) (70 angina pectoris, 108 myocardial infarction), whose serum ACE levels were concomitantly measured. Polymorphism of the ACE gene was characterized by three genotypes: two deletion alleles (genotype DD), two insertion alleles (genotype II), and heterozygous alleles (genotype ID). No differences could be detected among the three genotypes for total cholesterol, HDL cholesterol, and body mass index. Serum ACE levels were 11.4 +/- 2.7, 14.5 +/- 3.5, and 16.6 +/- 4.6 IU/mL for genotypes II, ID, and DD, respectively. In the study population, the genotype DD was more closely associated with CAD than the other two genotypes (ID and II). The frequency of deletion alleles was higher (0.58) in the CAD group than in healthy control subjects (0.42) (P < .05). Furthermore, multivessel disease was more strongly associated with deletion alleles than with insertion alleles (P < .05). CONCLUSIONS A deletion polymorphism of the ACE gene is associated with serum ACE activity and increased risk for CAD in the Japanese.

Plasma brain natriuretic peptide concentrations predict survival after acute myocardial infarction.

OBJECTIVES This study sought to examine whether plasma brain natriuretic peptide levels can predict prognosis after myocardial infarction. BACKGROUND It has been suggested that concentrations of plasma brain natriuretic peptide reflect left ventricular function. Although the prognosis after myocardial infarction depends on residual left ventricular function, it is not known whether plasma levels of brain natriuretic peptide after the onset of myocardial infarction can be used to predict long-term outcome. METHODS Plasma brain natriuretic peptide and atrial natriuretic peptide levels as well as invasive hemodynamic variables were measured in 70 patients with acute myocardial infarction (53 men, 17 women; mean age 65 years). Measurements were obtained on admission (mean 6 h after onset) and on day 2 after onset. Mean follow-up period was 18 months. RESULTS Plasma brain natriuretic peptide levels measured on admission and day 2 correlated significantly with hemodynamic variables, which are influenced by left ventricular function. However, plasma atrial natriuretic peptide levels correlated with none of the hemodynamic variables measured on admission; and of those measured on day 2, plasma atrial natriuretic peptide levels correlated only with left atrial filling pressure. During the follow-up period (mean 18 +/- 7 months), 11 patients died of cardiac causes. By Kaplan-Meier analysis, it was found that patients with plasma brain natriuretic peptide levels higher than the median level, both on admission and on day 2, had significantly higher mortality rates than those with the submedian level (on admission, p < 0.01; on day 2, p < 0.05). However, only the plasma atrial natriuretic peptide level obtained immediately after admission was significantly related to survival (p < 0.01). By Cox proportional hazards model analysis of the noninvasive variables, it was found that plasma brain natriuretic peptide concentration was more closely related to survival after myocardial infarction (p = 0.0001). CONCLUSIONS Increased plasma brain natriuretic peptide concentrations in the early or subacute phase of myocardial infarction are a powerful noninvasive indicator of poor prognosis, possibly reflecting residual left ventricular function after myocardial infarction.

Potent and Long-Lasting Vasodilatory Effects of Adrenomedullin in Humans Comparisons Between Normal Subjects and Patients With Chronic Heart Failure

BACKGROUND Adrenomedullin (ADM) is a recently discovered hypotensive peptide that has been isolated from human pheochromocytoma cells. Observations that ADM is produced from cardiovascular tissue and is found in plasma suggest that it may be important in the regulation of regional vascular resistance. METHODS AND RESULTS Limb vascular responses to ADM were examined in 10 healthy subjects and compared with those in 18 patients with chronic heart failure (CHF). The peptide increased forearm blood flow (FBF) from 2.7 +/- 0.3 to 11.8 +/- 0.9 mL.min-1.100 mL-1 in the control group and from 2.4 +/- 0.3 to 6.5 +/- 0.7 mL.min-1.100 mL-1 in the CHF group. The ADM-induced FBF increase was significantly impaired in the CHF group (P < .01). After cessation of the infusion, an increased FBF level was sustained for > 60 minutes in the control group, whereas in the CHF group the response returned to the baseline in < 30 minutes. The ADM infusion increased forearm skin blood flow in both groups (P < .05), whereas the skin blood flow response was impaired in the CHF group (P < .01). The role of nitric oxide in ADM-induced vasorelaxation was also studied in 11 healthy subjects and 6 patients with CHF. FBF and skin blood flow responses during ADM administration were significantly attenuated by NG-monomethyl-L-arginine administration in healthy control subjects (P < .05), whereas both flow responses remained the same in the CHF group. CONCLUSIONS These observations demonstrate that ADM exerts a potent and long-lasting vasodilatory effect on skeletal muscle arteries with involvement of nitric oxide-dependent mechanisms in normal human peripheral vasculature and that these vascular effects are significantly attenuated in patients with CHF, in part because of impaired production of nitric oxide in the forearm resistance vessels.

Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART).

OBJECTIVES We sought to assess the effects of low density lipoprotein (LDL)-apheresis (LDL-A) for regression of coronary plaque in familial hypercholesterolemia (FH), we set up a one-year follow-up multicenter trial using coronary angiography and intravascular ultrasound (IVUS). BACKGROUND It is still unclear whether aggressive lipid-lowering therapy by LDL-A leads to the regression of coronary plaque in patients with FH. METHODS Eighteen patients with FH were assigned to one of two groups: medication + LDL-A (LDL-A group, n = 11) and medication only (medication group, n = 7). Total cholesterol, triglycerides, high density lipoprotein cholesterol and LDL cholesterol were measured in all subjects at the outset of treatment (baseline) and every three months thereafter. Coronary angiography and IVUS were performed at the outset and after the one-year follow-up period to measure minimal lumen diameter (MLD) by coronary angiogram and plaque area (PA) by IVUS. RESULTS The LDL-A group showed 28.4% reduction in total cholesterol (from 275 +/- 27 mg/dl to 197 +/- 19 mg/dl) and 34.3% reduction in LDL cholesterol (from 213 +/- 25 mg/dl to 140 +/- 27 mg/dl) after one-year follow-up, while the medication group showed no changes in cholesterol levels. There were significant interactions between both treatments in total cholesterol (p = 0.0001), LDL cholesterol (p = 0.0001), MLD (p = 0.008) and PA (p = 0.017) using two-way repeated-measures analysis of variance by the SAS system (SAS Institute Inc., Cary, North Carolina). Significant differences were seen in net change in MLD (p = 0.004) and PA (p = 0.008) during the one-year follow-up period between both groups. CONCLUSIONS These results suggest that aggressive lipid-lowering therapy using the combination of LDL-A and lipid-lowering drugs may induce regression of coronary atherosclerotic plaque in FH patients.

Value of plasma B type natriuretic peptide measurement for heart disease screening in a Japanese population

Background: Conflict exists regarding the usefulness of measuring plasma B type natriuretic peptide (BNP) concentrations for identifying impaired left ventricular (LV) systolic function during mass screening. Various cardiac abnormalities, regardless of degree of LV dysfunction, are prone to carry a high risk of cardiovascular events. Objective: To examine the validity of plasma BNP measurement for detection of various cardiac abnormalities in a population with a low prevalence of coronary heart disease and LV systolic dysfunction. Design and setting: Participants in this cross sectional study attended a health screening programme in Iwate, northern Japan. Plasma BNP concentrations were determined in 1098 consecutive subjects (mean age 56 years) by direct radioimmunoassay. All subjects underwent multiphasic health checkups including physical examination, ECG, chest radiography, and transthoracic echocardiography. Results: Conventional diagnostic methods showed 39 subjects to have a wide range of cardiac abnormalities: lone atrial fibrillation or flutter in 11; previous myocardial infarction in seven; valvar heart disease in seven; hypertensive heart disease in six; cardiomyopathy in six; atrial septal defect in one; and cor pulmonale in one. No subjects had a low LV ejection fraction (< 40%). To assess the utility of plasma BNP measurement for identification of such patients, receiver operating characteristic analysis was performed. The optimal threshold for identification was a BNP concentration of 50 pg/ml with sensitivity of 89.7% and specificity of 95.7%. The area under the receiver operating characteristic curve was 0.970. The positive and negative predictive values at the cutoff level were 44.3% and 99.6%, respectively. Conclusion: Measurement of plasma BNP concentration is a very efficient and cost effective mass screening technique for identifying patients with various cardiac abnormalities regardless of aetiology and degree of LV systolic dysfunction that can potentially develop into obvious heart failure and carry a high risk of a cardiovascular event.

Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-Alpha in Myocardium in Human Dilated Cardiomyopathy

OBJECTIVES We examined the mRNA expression and protein localization of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in myocardial tissue obtained from patients with dilated cardiomyopathy (DCM). BACKGROUND The etiology of DCM is unknown, but viral infection or autoimmune abnormalities that induce cytokine expression have been proposed as pathogenetic factors. Nitric oxide (NO), synthesized by nitric oxide synthase (NOS), has negative inotropic and cytotoxic effects on cardiomyocytes. Cytokines such as TNF-alpha are potent stimulators of iNOS expression. Expression of iNOS leads to excessive production of NO in the myocardium and may modulate cardiac contractility and ventricular morphology. METHODS We examined the mRNA expression and protein localization of iNOS and TNF-alpha in myocardial tissue obtained from 24 patients with DCM, 20 patients with hypertrophic cardiomyopathy (HCM) and 15 control subjects, using the reverse transcriptase-polymerase chain reaction method and immunohistochemical studies. We then compared the differences in clinical characteristics between DCM patient subgroups with and without myocardial iNOS expression. RESULTS Messenger RNA expression of iNOS and TNF-alpha was observed, respectively, in 13 (54%) and 18 (75%) patients with DCM. Gene expression of TNF-alpha was consistently detected in endomyocardial tissue from patients with DCM and INOS expression. Inducible NOS protein was evident only in cardiomyocytes, whereas TNF-alpha was apparent in both cardiomyocytes and endomyocardial endothelium. Neither mRNA expression nor protein localization of iNOS or TNF-alpha was observed in cardiac tissue obtained from patients with HCM or control subjects. Patients with DCM and iNOS mRNA showed a lower left ventricular ejection fraction (p < 0.01) and a higher left ventricular volume (p < 0.05) than the negative DCM group. CONCLUSIONS Inducible NOS was consistently coexpressed with TNF-alpha in myocardial tissue obtained from a subgroup of patients with DCM and advanced left ventricular dysfunction.

Tumor Necrosis Factor-α–Converting Enzyme and Tumor Necrosis Factor-α in Human Dilated Cardiomyopathy

Background—Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). TNF-α–converting enzyme (TACE) has recently been purified and its complementary DNA cloned. The expression of TACE results in the production of a functional enzyme that has precursor TNF-α in the mature form. The aim of this study was to determine whether TACE is expressed with TNF-α in myocardium and whether levels of TACE and TNF-α are related to clinical severity of DCM. Methods and Results—Endomyocardial tissues were obtained from 30 patients with DCM and 5 control subjects. TNF-α and TACE mRNA levels were measured by a novel real-time quantitative reverse transcriptase–polymerase chain reaction method. Expression of TNF-α and TACE proteins was determined by immunohistochemical analysis. TNF-α mRNA was expressed in DCM patients (TNF-α/GAPDH ratio 0.85±0.24) but not in control subjects. TACE mRNA expression was significantly greater in DCM patients than in control subjects (TACE/GAPDH rat...

Predictors of sinus rhythm restoration after cox maze procedure concomitant with other cardiac operations

BACKGROUND There have been sporadic cases of persistent atrial fibrillation and sick sinus syndrome after the maze procedure. The purpose of this study was to identify the predictors of sinus rhythm restoration after operation. METHODS Between March 1993 and June 1995, we evaluated retrospectively 96 consecutive patients who underwent the maze procedure (maze III) in combination with another type of cardiac operation. Four patients who died and 6 patients who required permanent pacemaker implantation because of sick sinus syndrome were excluded. Ambulatory electrocardiographic monitoring was evaluated 1 year after operation. Multiple logistic regression analysis was applied to identify the predictors of sinus rhythm restoration. RESULTS The final population comprised 86 patients (mean age, 59.8 years; 67 patients with mitral valve disease). Overall, sinus rhythm was restored in 68 of 86 patients (79.1%). The magnitude of the atrial fibrillatory wave positively predicted postoperative sinus rhythm restoration. Conversely, left atrial diameter was inversely related to postoperative sinus rhythm restoration. The odds ratio of having both a fine atrial fibrillatory wave (< 1.0 mm) and enlarged left atrial diameter (> or = 65 mm) for patients with sinus rhythm restoration was 0.04 (95% confidence interval, 0.01 to 0.28). CONCLUSIONS Atrial fibrillatory wave and left atrial diameter were independent predictors of sinus rhythm restoration after the maze procedure in patients with chronic atrial fibrillation and organic heart disease.

The Association of C-Reactive Protein Levels With Carotid Intima-Media Complex Thickness and Plaque Formation in the General Population

Background and Purpose— An inflammatory response has been associated with the development of atherosclerosis. Our aim was to clarify which atherosclerotic changes (intima-media complex thickness [IMT] increase, plaque formation, and arterial dilatation) are associated with C-reactive protein (CRP) levels and to determine whether there are any gender differences. Methods— Carotid ultrasound and measurement of high-sensitivity CRP (hs-CRP) levels were performed in 2056 subjects selected from a general population (mean age 58.3 years; 1290 men). Results— In both genders, IMT significantly increased with increasing hs-CRP quartile (P<0.001), but this relationship disappeared after adjustment for age and other traditional cardiovascular risk factors. In men, but not women, carotid luminal diameter significantly increased with increasing hs-CRP levels (P<0.05), but again, this relationship disappeared with adjustment for age and other risk factors. However, in men, but not women, plaque score increased significantly with increasing hs-CRP quartile (P<0.01), even after adjustment for age and other traditional risk factors. Conclusions— CRP level was closely associated with early atherosclerotic changes represented by carotid plaque formation. However, the IMT increase was strongly associated with aging and other traditional cardiovascular risk factors rather than CRP level. In the general population, CRP may serve as a complementary and quantitative marker for atherosclerotic plaque formation in men but not women.

Relationship between Plasma Level of Brain Natriuretic Peptide and Myocardial Infarct Size

To investigate the clinical significance of plasma brain natriuretic peptide (BNP) measurement in patients with acute myocardial infarction (MI), circulating levels of BNP, atrial natriuretic peptide, creatine kinase (CK), and hemodynamic parameters were serially determined in 24 patients with a first episode of acute MI. Plasma BNP (mean +/- SEM) gradually increased and peaked 21 h after the onset (from 13.7 +/- 2.2 to 23.0 +/- 3.3 fmol/ml; p < 0.001). A significant correlation was found between the increase in plasma BNP level and both the peak CK level (r = 0.83; p < 0.05) and the MI size (r = 0.74; p < 0.05). The increase in plasma BNP in the acute phase was found to be a significant predictor of left ventricular (LV) function evaluated in the convalescent phase (LV ejection fraction, r = -0.63; p < 0.05, LV end-diastolic pressure, r = 0.56; p < 0.05). In conclusion, in patients with acute MI, increases in plasma BNP concentration during the early phase reflect MI size, and thereby may predict later LV function.