Iku Toda

Brain natriuretic peptide as a cardiac hormone in essential hypertension

PURPOSE A natriuretic peptide, brain natriuretic peptide (BNP), has been isolated from porcine hearts. We performed this study to determine if BNP is secreted from the heart and to identify changes, if any, in the plasma BNP concentration in essential hypertension. PATIENTS AND METHODS We measured the immunoreactive (ir) BNP concentration at intracardiac sites including the coronary sinus of five patients with heart disease during cardiac catheterization. We examined plasma ir-BNP in 48 hypertensive patients, 15 borderline hypertensive patients, and 25 normotensive subjects. RESULTS Plasma ir-BNP in the coronary sinus was greater than at other cardiac sites. The concentration was significantly higher in hypertensive subjects than in borderline hypertensive or normotensive subjects. Hypertensive patients with left ventricular hypertrophy (LVH) established by echocardiography had higher plasma ir-BNP levels than those without LVH. In the hypertensive group, plasma ir-BNP was closely correlated with the LV mass index. In these patients, BNP levels were correlated with mean arterial pressure and inversely correlated with the LV ejection fraction, although these correlations were weak. Reverse-phase high-pressure liquid chromatography showed that the major component of circulating ir-BNP in the hypertensive and normotensive subjects corresponded to authentic human BNP-32. CONCLUSIONS Human BNP-32 was secreted through the coronary sinus from the heart and may act as a cardiac hormone. Plasma BNP was increased in many of the hypertensive subjects with LVH. The increase in BNP seemed to be related to LVH or the cardiac overload associated with LVH.

Circulating immunoreactive endothelin in ischemic heart disease

Circulating immunoreactive endothelin (ir-ET) was measured in nine patients with acute myocardial infarction (AMI), 10 patients with stable angina pectoris (SAP), and 25 normal control subjects. In patients with AMI, the plasma ir-ET level was elevated in the acute phase and was highest on the day of onset (AMI: 3.8 +/- 1.7 pg/ml, normal control value: 0.5 +/- 0.2 pg/ml). The plasma ir-ET level showed a positive correlation with the wall motion abnormality index (rs = 0.56, p less than 0.01), thrombin-antithrombin III complex (rs = 0.55, p less than 0.01), and beta thromboglobulin (rs = 0.39, p less than 0.05). An especially high plasma ir-ET level was detected in patients in whom the Killip subset was IV. The plasma ir-ET level was not increased in patients with SAP (0.8 +/- 0.3 pg/ml). The plasma ir-ET level is increased in the acute phase of AMI. A pathophysiologic state characterized by cardiac dysfunction, an activated coagulation system, and platelet hyperactivity may be associated with this increase in plasma ir-ET.

Tissue Doppler-derived index of left ventricular filling pressure, E/E′, predicts survival of patients with non-valvular atrial fibrillation

Objectives: To investigate whether the ratio of early transmitral flow velocity (E) to early diastolic mitral annular velocity (E′) predict prognosis in patients with non-valvular atrial fibrillation. Methods: 230 patients with non-valvular atrial fibrillation were enrolled and studied. According to E/E′ value, patients were divided into groups with lower (group A with E/E′ ⩽ 15) and higher (group B with E/E′ > 15) E/E′. Results: During follow up (average 245 days), 21 (9.1%) deaths were documented. All cause death (15/90 (16.7%) v 6/140 (4.3%)), cardiac death (10 (11.1%) v 2 (1.4%)) and congestive heart failure (16 (17.8%) v 8 (5.7%)) were more common in group B than in group A (all p < 0.01). A Kaplan–Meier survival curve showed that the cumulative survival rate was significantly lower in group B than in group A (log rank p  =  0.0013). By multivariate logistic regression analysis, E/E′ (χ2  =  4.47, odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.11, p  =  0.03) and age (χ2  =  6.45, OR 1.06, 95% CI 1.01 to 1.11, p  =  0.02) were independent predictors of mortality. Conclusion: The Doppler-derived index of left ventricular filling pressure, E/E′, is a powerful predictor of the clinical outcome of patients with non-valvular atrial fibrillation.

The complement system in ischemic heart disease.

The mechanisms by which tissue injury after acute myocardial infarction (AMI) occurs has not been fully elucidated. Recent evidence in experimental models has suggested involvement of the complement system in microvascular and macrovascular injury subsequent to AMI. With respect to angina pectoris, whether or not the complement system is activated is not clear. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation, including C3d, C4d, Bb, and SC5b-9 complexes, in 31 patients with AMI, 17 patients with unstable angina pectoris, 19 patients with stable angina pectoris, and 20 normal volunteers. The plasma C3d levels increased in patients with AMI and in those with unstable angina pectoris (p less than 0.01). The plasma levels of C4d, Bb, and SC5b-9 increased only in patients with AMI (p less than 0.01). The plasma SC5b-9 level was related to peak creatine phosphokinase (r = 0.71) and inversely related to the ejection fraction (r = -0.71). The plasma SC5b-9 level of patients with congestive heart failure was higher than that of patients without congestive heart failure in AMI. These results show that activation of complement system occurs after AMI and show an association of myocardial damage with complement activation. With respect to angina pectoris, the complement system is mildly activated in patients with unstable angina pectoris; however, the cardiac function of patients with unstable angina pectoris is not damaged. The complement system of patients with stable angina pectoris is not activated.

Cardioprotective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-reperfusion injury

We investigated the protective effect of angiotensin II (Ang II) type 1 receptor antagonist on myocardial ischemia-reperfusion injury and the role of exogenous Ang II to this injury in perfused hearts. We orally administered TCV-116 (Ang II type 1 receptor antagonist) and delapril (angiotensin converting enzyme inhibitor) to Wistar rats for 1 week and measured the immunoreactive cardiac Ang II. Immunoreactive cardiac Ang II (pg/gm tissue) was 14.3 +/- 2.0 in control group, 11.8 +/- 0.8 in TCV-116-treated group, and 7.3 +/- 0.6 in delapril-treated group (p < 0.05 compared to TCV-116-treated group; p < 0.01 compared to control group). The 15 hearts (five rats in each group) were perfused by a langendorff method and global ischemia was maintained for 30 min. Both TCV-116 and delapril were found to improve postischemic cardiac function and decrease reperfusion creatine kinase (CK) release. Ang II injection before ischemia worsened postischemic cardiac function and increased reperfusion CK release. Only TCV-116 prevented this injury. These data indicated that TCV-116 Ang II type 1 receptor antagonist was effective against myocardial ischemia-reperfusion injury, and exogenous Ang II accelerated this injury through Ang II type 1 receptor.

Circulating immunoreactive endothelin in patients undergoing percutaneous transluminal coronary angioplasty

Circulating immunoreactive endothelin (ir-ET) in the coronary sinus (CS) and the femoral artery (Ao) was measured in patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Plasma ir-ET level in the CS was significantly increased from 1.6 +/- 0.8 pg/mL to 2.0 +/- 1.0 pg/mL after PTCA (P less than .05). Plasma ir-ET level in the Ao tended to increase after PTCA, but it was not significant. Plasma ir-ET level in the CS was not related to the plasma thromboglobulin level, plasma thrombin-antithrombin complex level, mean blood pressure, or heart rate. These results suggest that the increase of plasma ir-ET level in the CS may be associated with the coronary endothelial injury by PTCA.

Inhibition by angiotensin II type 1 receptor antagonist of cardiac phenotypic modulation after myocardial infarction

The purpose of this study was to examine the cardiac phenotype and remodeling after myocardial infarction and the effect of the angiotensin II type 1 (AT1) receptor antagonist (TCV-116) on the gene expression. Myocardial infarction in rats was produced by ligation of the coronary artery. TCV-116 (10 mg/kg/day) was administered orally to rats from 1 day after myocardial infarction. At 1, 2 and 3 weeks after myocardial infarction, blood pressure and heart rate were measured, and the heart was removed. The left ventricle was measured for infarct size and weight, and then the total RNA from the non-ischemic left ventricle was extracted. mRNAs in the non-ischemic left ventricle were measured by Northern blot analysis. The weight of the non-ischemic left ventricle was significantly increased 3 weeks after infarction. This was completely prevented by TCV-116 treatment. mRNA levels for beta-myosin heavy chain (beta-MHC), atrial natriuretic polypeptide (ANP), collagen types I and III and transforming growth factor-beta 1 (TGF-beta 1) in the non-ischemic left ventricle were increased by a factor of 3.0, 6.7, 7.9, 4.0 and 1.4 (P < 0.01), respectively, 1 week after infarction. There was no increase in alpha-skeletal actin mRNA at 1 and 2 weeks, but it was increased by a factor of 2.9 (P < 0.05) at 3 weeks. On the other hand, there was no change in alpha-MHC mRNA during the 3 weeks. TCV-116 significantly suppressed the increased gene expression of beta-MHC and alpha-skeletal actin in the non-ischemic myocardium at all time points, and also suppressed the expression of ANP at 2 and 3 weeks. However, TCV-116 failed to inhibit the expression of collagen I and III mRNAs at 1 and 3 weeks. These results show that myocardial infarction causes a rapid shift of myocytes to fetal phenotype and a rapid activation of collagen genes in the non-ischemic myocardium. AT1 receptor may be responsible for the phenotypic modulation of myocytes following myocardial infarction.

Age- and Gender-Specific Changes in the Left Ventricular Relaxation A Doppler Echocardiographic Study in Healthy Individuals

Background—Although left ventricular diastolic function has been shown to deteriorate with advancing age, its gender-specific change is unknown. The aim of this study was to investigate age- and gender-specific changes in tissue Doppler–derived left ventricular diastolic index, E′. Methods and Results—A total of 1333 healthy individual without known heart disease or hypertension (mean age, 55 years; range, 10 to 89) were enrolled and studied. Peak early mitral annular velocity (E′) and peak late mitral annular velocity (A′) were recorded and measured. As an index of the left ventricular relaxation, E′ was used. As an index of the left ventricular filling pressure, E/E′ was calculated. Although systolic indices poorly correlated with age, diastolic indices correlated well with age. Among those aged 30 to 39 and 40 to 49 years, E′ was significantly lower in males than in females. In subjects aged 50 to 59 and 60 to 69 years, E′ was similar in both genders. Among those aged 70 to 79 and 80 to 89 years, E′ was significantly lower in females than in males. Predictors of the lowest quartile of E′ among subjects aged >50 years were age (P<0.0001; &khgr;2=66.11; odds ratio, 1.08; 95% CI, 1.058 to 1.097) and female gender (P=0.002; &khgr;2=9.23; odds ratio, 1.68; 95% CI, 1.202 to 2.343). Conclusion—Age-related changes in diastolic indices were gender specific. In the elderly population, diastolic function deteriorated more significantly in the female gender than in the male gender. These results may explain the relatively higher incidence in elderly females among patients with diastolic heart failure and higher cardiovascular mortality in the female gender.Background— Although left ventricular diastolic function has been shown to deteriorate with advancing age, its gender-specific change is unknown. The aim of this study was to investigate age- and gender-specific changes in tissue Doppler–derived left ventricular diastolic index, E′. Methods and Results— A total of 1333 healthy individual without known heart disease or hypertension (mean age, 55 years; range, 10 to 89) were enrolled and studied. Peak early mitral annular velocity (E′) and peak late mitral annular velocity (A′) were recorded and measured. As an index of the left ventricular relaxation, E′ was used. As an index of the left ventricular filling pressure, E/E′ was calculated. Although systolic indices poorly correlated with age, diastolic indices correlated well with age. Among those aged 30 to 39 and 40 to 49 years, E′ was significantly lower in males than in females. In subjects aged 50 to 59 and 60 to 69 years, E′ was similar in both genders. Among those aged 70 to 79 and 80 to 89 years, E′ was significantly lower in females than in males. Predictors of the lowest quartile of E′ among subjects aged >50 years were age ( P <0.0001; χ2=66.11; odds ratio, 1.08; 95% CI, 1.058 to 1.097) and female gender ( P =0.002; χ2=9.23; odds ratio, 1.68; 95% CI, 1.202 to 2.343). Conclusion— Age-related changes in diastolic indices were gender specific. In the elderly population, diastolic function deteriorated more significantly in the female gender than in the male gender. These results may explain the relatively higher incidence in elderly females among patients with diastolic heart failure and higher cardiovascular mortality in the female gender. Received July 22, 2008; accepted October 30, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Effects of Candesartan and Cilazapril on Rats With Myocardial Infarction Assessed by Echocardiography

The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2+/-0.6 and 26.3+/-2. 6 m/s2 at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of beta-myosin heavy chain, alpha-skeletal actin, and atrial natriuretic peptide in noninfarcted ventricle at 1 and 4 weeks and expression of collagen I and III at 4 weeks to a similar extent. When given at a dose of 10 mg/kg per day, both candesartan and cilazapril prevented cardiac dysfunction and gene expression to the same extent as when given at 1 mg/kg per day. In conclusion, Doppler echocardiography showed that candesartan and cilazapril equally improved systolic and diastolic function and that ventricular remodeling accompanied modulation of cardiac gene expression.

A Prospective, Multicenter, Randomized Trial to Assess Efficacy of Pioglitazone on In-Stent Neointimal Suppression in Type 2 Diabetes : POPPS (Prevention of In-Stent Neointimal Proliferation by Pioglitazone Study)

OBJECTIVES The aim of this study was to clarify whether pioglitazone suppresses in-stent neointimal proliferation and reduces restenosis and target lesion revascularization (TLR) after percutaneous coronary intervention (PCI). BACKGROUND Previous single-center studies have demonstrated the anti-restenotic effect of a peroxisome proliferator-activated receptor gamma agonist, pioglitazone, after PCI. METHODS A total of 97 patients with type 2 diabetes mellitus (T2DM) undergoing PCI (bare-metal stents only) were enrolled. After PCI, patients were randomly assigned to either the pioglitazone group (n = 48) or the control group (n = 49). Angiographical and intravascular ultrasound (IVUS) imaging were performed at baseline and repeated at 6-month follow-up. Primary end points included angiographical restenosis and TLR at 6 months follow-up. Secondary end point was in-stent neointimal volume by IVUS. RESULTS Baseline glucose level and glycosylated hemoglobin (HbA1c) level were similar between the pioglitazone group and the control group. Angiographical restenosis rate was 17% in the pioglitazone group and 35% in control group (p = 0.06). The TLR was significantly lower in pioglitazone group than in control group (12.5% vs. 29.8%, p = 0.04). By IVUS (n = 56), in-stent neointimal volume at 6 months showed a trend toward smaller in the pioglitazone group than in the control group (48.0 +/- 30.2 mm(3) vs. 62.7 +/- 29.0 mm(3), p = 0.07). Neointimal index (neointimal volume/stent volume x 100) was significantly smaller in the pioglitazone group than in the control group (31.1 +/- 14.3% vs. 40.5 +/- 12.9%, p = 0.01). CONCLUSIONS Pioglitazone treatment might suppress in-stent neointimal proliferation and reduce incidence of TLR after PCI in patients with T2DM.