Tomomi Meguro

Effect on short-term prognosis and left ventricular function of angina pectoris prior to first Q-wave anterior wall acute myocardial infarction

The prognostic significance of angina pectoris before the development of first Q-wave anterior wall acute myocardial infarction (AMI) was assessed in 153 patients. A total of 100 patients in this study had angina before Q-wave AMI, whereas 53 patients had no antecedent symptoms of angina. The presence of angina before AMI was associated with a lower incidence of complications including sustained ventricular tachycardia or fibrillation (7% vs 25%, p = 0.0022), pump failure (24% vs 47%, p = 0.0035), cardiac rupture (1% vs 17%, p = 0.0001), and a lower in-hospital mortality rate (11% vs 28%, p = 0.0067). The peak creatine phosphokinase activity was lower in patients with than without antecedent angina (1,727 +/- 1,238 vs 2,675 +/- 2,569 IU/liter, respectively, p = 0.023). There was no difference in the prevalence of multivessel coronary artery disease or the presence of collateral circulation between the 2 groups. Left ventriculography revealed a higher left ventricular ejection fraction (54 +/- 13% vs 46 +/- 11%, p = 0.034) and smaller left ventricular end-diastolic volumes (75 +/- 15 vs 86 +/- 18 ml/m2, p = 0.017) in patients with than without antecedent angina. These findings suggest that the presence of angina before AMI may be associated with a protective effect on left ventricular function during anterior wall AMI. Although the precise mechanisms underlying the beneficial effects are unknown, they may be related to the development of collateral channels or ischemic preconditioning.

Persistent Cardiac Aldosterone Synthesis in Angiotensin Ii Type 1a Receptor–knockout Mice After Myocardial Infarction

Background—The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)–dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II–independent remodeling is unclear. Methods and Results—Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor–knockout (AT1A-KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT1A-KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT1A-KO mice. In AT1A-KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized. Conclusions—Our results indicate that genetic blockade of AT1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II–independent mechanisms.

C-Reactive Protein Overexpression Exacerbates Pressure Overload–Induced Cardiac Remodeling Through Enhanced Inflammatory Response

Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload–induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa &agr;-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47phox), and collagen-I, the number of infiltrating Mac-2–positive macrophages, nuclear localization of phosphorylated NF-&kgr;B/p65 (p-p65) in cardiomyocytes, nuclear NF-&kgr;B-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, IL-6, GPx3, p47phox, collagen-I, and transforming growth factor (TGF)-&bgr;1, the protein level of TGF-&bgr;1, and the numbers of Mac-2–positive macrophages and p-p65–positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload–induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress.

Elevated troponin T on discharge predicts poor outcome of decompensated heart failure

Persistent elevation of cardiac troponin T (cTnT) predicts an adverse clinical outcome in patients with chronic heart failure (HF), but the underlying mechanisms remain to be determined. We investigated the association between predischarge cTnT elevation and coexistent pathophysiology in patients with decompensated HF. Plasma cTnT levels were determined before discharge in 170 patients with decompensated HF. We divided the patients into a group that was positive for cTnT [cTnT(+) group, n = 40] and a group that was negative for cTnT [cTnT(−) group, n = 130]. Multivariate analysis showed that use of β-blocker therapy (odds ratio [OR] = 0.236, P = 0.003), an elevated high-sensitivity C-reactive protein (hsCRP) level (OR = 3.731, P = 0.006), a high brain natriuretic peptide (BNP) level (OR = 3.570, P = 0.007), diabetes (OR = 3.090, P = 0.018), and anemia (OR = 2.330, P = 0.047) were independently associated with cTnT positivity. During a mean follow-up period of 441 days after discharge, total mortality (P < 0.001), cardiac death (P < 0.001), and exacerbation of HF requiring hospitalization (P = 0.007) were all more common in the cTnT(+) group than in the cTnT(−) group. Cox proportional hazards analysis showed that cTnT positivity was an independent predictor of total mortality (hazard ratio = 5.008, P = 0.004) in an age- and gender-matched model. Elevation of cTnT during convalescence was associated with lack of β-blocker therapy, a high hsCRP level at discharge, a high BNP level at discharge, diabetes, and anemia, and a worse clinical outcome in patients with decompensated HF.

Significance of AT1 Receptor Independent Activation of Mineralocorticoid Receptor in Murine Diabetic Cardiomyopathy

Background Diabetes mellitus (DM) has deleterious influence on cardiac performance independent of coronary artery disease and hypertension. The objective of the present study was to investigate the role of the renin-angiotensin-aldosterone system, especially angiotensin II type 1a receptor (AT1aR) and mineralocorticoid receptor (MR) signaling, in left ventricular (LV) dysfunction induced by diabetes mellitus (DM). Methods and Results DM was induced by intraperitoneal injection of streptozotocin (200 mg/kg BW) in wild-type (WT) or AT1aR knockout (KO) male mice, and they were bred during 6 or 12 weeks. Some KO mice were administered the MR antagonist eplerenone (100 mg/kg body weight). At 6 weeks, LV diastolic function was impaired in WT-DM, but preserved in KO-DM. At that time point MR mRNA expression was upregulated, NADPH oxidase subunit (p47phox) and glutathione peroxidase (GPx1) mRNA expression were upregulated, the staining intensities of LV tissue for 4-hydroxy-2-nonenal was stronger in immunohistochemistry, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells was increased, Bcl-2 protein expression was significantly downregulated, and the expression of SERCA2a and phosphorylated phospholamban was depressed in WT-DM, while these changes were not seen in KO-DM. At 12 weeks, however, these changes were also noted in KO-DM. Eplerenone arrested those changes. The plasma aldosterone concentration was elevated in WT-DM but not in KO-DM at 6 weeks. It showed 3.7-fold elevation at 12 weeks even in KO-DM, which suggests “aldosterone breakthrough” phenomenon. However, the aldosterone content in LV tissue was unchanged in KO-DM. Conclusions DM induced diastolic dysfunction was observed even in KO at 12 weeks, which was ameliorated by minelarocorticoid receptor antagonist, eplerenone. AT1-independent MR activation in the LV might be responsible for the pathogenesis of diabetic cardiomyopathy.

Usefulness of accelerated diastolic reversed flow along the left ventricular posterior wall in aortic regurgitation for estimating left ventricular function

Abstract Timely indication of surgical correction of aortic regurgitation (AR) depends on precise evaluation of left ventricular (LV) function. However, it may still be difficult to accurately predict surgical outcome with only currently available indexes of LV function. We undertook this study to obtain a novel index of LV function from altered LV fluid dynamics in patients with AR. AR flow is expected to cause definitive changes in intraventricular flow distributions. The degree of such changes may be mainly determined by the severity of regurgitation but variously affected by chamber size, diastolic property and filling pressure of the left ventricle. Therefore, our hypothesis is that the changes in the intraventricular fluid dynamics reflect LV function in patients with similar degrees of AR. We tested this hypothesis in patients with severe AR using the Doppler ultrasound technique and obtained a novel index for estimating LV function.

Atrophy of the parahippocampal gyrus is prominent in heart failure patients without dementia

The exacerbation of heart failure (HF) induces brain damage and cognitive impairment (CI), which frequently attenuates the effects of treatment. However, it is not clear whether HF patients without clinical dementia demonstrate increased risk of CI. We examined whether local atrophy in the parahippocampal gyrus, a potential predictor of CI, is prominent in HF patients without clinical dementia.